U.S. patent number 9,675,478 [Application Number 14/302,295] was granted by the patent office on 2017-06-13 for solvent method for forming a polymer scaffolding.
This patent grant is currently assigned to Abbott Cardiovascular Systems Inc.. The grantee listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Ni Ding, Stephen D. Pacetti.
United States Patent |
9,675,478 |
Pacetti , et al. |
June 13, 2017 |
Solvent method for forming a polymer scaffolding
Abstract
Methods of making polymeric devices, such as stents, using
solvent based processes. More particularly, methods of making
bioabsorbable stents.
Inventors: |
Pacetti; Stephen D. (San Jose,
CA), Ding; Ni (San Jose, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
Abbott Cardiovascular Systems
Inc. (Santa Clara, CA)
|
Family
ID: |
53487436 |
Appl.
No.: |
14/302,295 |
Filed: |
June 11, 2014 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20150359647 A1 |
Dec 17, 2015 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F
2/90 (20130101); A61L 31/06 (20130101) |
Current International
Class: |
A61F
2/91 (20130101); A61L 31/06 (20060101); A61F
2/90 (20130101); A61F 2/82 (20130101) |
Field of
Search: |
;427/2.1,2.24,2.25,337,372.2 ;623/1.15,1.16 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Cryogenic Grinding,
http://en.wikipedia.org/wiki/Cryogenic.sub.--grinding, printed Sep.
17, 2014, 2 pages. cited by applicant .
Molar Mass Distribution,
http://en.wikipedia.org/wiki/Molar.sub.--mass.sub.--distribution,
printed May 16, 2014, 4 pages. cited by applicant .
Sintering, http://en.wikipedia.org/wiki/Sintering, printed May 21,
2014, 15 pages. cited by applicant .
Viscosity, http://en.wikipedia.org/wiki/Viscosity, printed Jun. 6,
2014, 24 pages. cited by applicant .
International Search Report and Written Opinion of the
International Searching Authority mailed on Nov. 9, 2015, for
International Patent Application No. PCT/US2015/035171, 25 pp.
cited by applicant .
Non-Final Rejection in U.S. Appl. No. 14/304,792, mailed on Jul.
31, 2015; 9 pages. cited by applicant .
Notice of Allowance in U.S. Appl. No. 14/304,792, mailed on Nov.
12, 2015; 5 pages. cited by applicant .
Supplemental Notice of Allowability in U.S. Appl. No. 14/304,792,
mailed on Jun. 9, 2016; 2 pages. cited by applicant.
|
Primary Examiner: Sellman; Cachet
Attorney, Agent or Firm: Squire Patton Boggs (US) LLP
Claims
What is claimed is:
1. A method of making a stent body for supporting a vascular lumen,
comprising providing or forming a polymer solution comprising a
solvent and a polymer with an inherent viscosity of at least 3.3
dl/g, a number average molecular weight greater than 250,000 g/mole
as measured by gel permeation chromatography using polystyrene
standards, or both; either (a) immersing a cylindrical member into
the polymer solution and removing the cylindrical member from the
polymer solution; wherein a portion of the polymer solution remains
on the surface of the cylindrical member upon removal from the
polymer solution; and removing at least a portion of the solvent
from the polymer solution remaining on the cylindrical member to
form a tubular layer of the polymer on the cylindrical member; or
(b) spraying the polymer solution onto the cylindrical member; and
substantially removing the solvent during, after, or both during
and after the spraying to form a tubular layer of the polymer on
the cylindrical member; optionally, repeating (a) on one or more
occasions, repeating (b) on one or more occasions, or both, with
repeating of the providing or forming prior to repeating (a), (b),
or both, being optional, to form a final tubular layer of polymer
on the cylindrical member of a desired thickness, removing residual
solvent from the final tubular layer; and forming a stent body from
the final tubular layer; wherein if the optional providing or
forming is repeated, for each repetition, the solvent, the polymer,
or both, of the polymer solution may be different from the polymer,
the solvent, or both used in the prior execution of (a), (b), or
both; and wherein removal of the residual solvent from the final
tubular layer comprises removal in an environment of solvent vapor,
the solvent of the solvent vapor being a removal solvent, where the
removal solvent is different from the solvent of the polymer
solution; and wherein the removal solvent is selected from the
group consisting of acetonitrile, methanol, ethanol, n-propanol,
isopropanol, butanol, fluoroform, freons, methylene chloride
(CH.sub.2Cl.sub.2), and combinations thereof.
2. The method of claim 1, wherein the environment of removal
solvent vapor is at a temperature not less than 30.degree. C. but
not more than the glass transition temperature of the polymer.
3. The method of claim 1, wherein the environment of removal
solvent vapor is at a temperature not less than the glass
transition temperature of the polymer, or not less than 28.degree.
C., if the glass transition temperature is lower than 25.degree.
C., and not more than the melting temperature of the polymer, if
the polymer has a melting temperature of at least 45.degree. C., or
not more than the higher of 50.degree. C. above the glass
transition temperature of the polymer, and 45.degree. C.
4. The method of claim 1, wherein the removal solvent plasticizes
the polymer.
5. The method of claim 1, wherein the removal solvent partial
pressure is at least 100 Torr.
6. The method of claim 1, wherein the removal solvent partial
pressure is at least 50% of the vapor pressure of the pure removal
solvent at the temperature of the environment.
7. The method of claim 1, wherein the removal of residual solvent
from the final tubular layer in an environment of removal solvent
vapor comprises placing the tubular layer in an environment of
solvent vapor for at least 0.2 hour and not more than 1,000
hours.
8. The method of claim 1, wherein the environment of removal
solvent vapor is at a pressure of 760 Torr.+-.100 Torr.
9. The method of claim 1, wherein the environment of removal
solvent vapor is at a pressure of not more than 380 Torr, but at
least 0.001 Torr.
10. The method of claim 1, wherein the removal solvent is selected
from the group consisting of acetonitrile, methanol, ethanol,
n-propanol, isopropanol, butanol, fluoroform, methylene chloride
(CH.sub.2Cl.sub.2), and combinations thereof.
11. A method of making a stent body for supporting a vascular
lumen, comprising: coating a web with a polymer solution comprising
a solvent and a polymer, wherein the polymer has an inherent
viscosity greater than 3.3 dl/g, has a weight average molecular
weight greater than 500,000 g/mole, or both; removing at least a
portion of the solvent from the polymer solution remaining on the
web to form a polymer film on the web; separating the polymer film
from the web; and wrapping the polymer film around a cylindrical
member, subject to the constraint that the edges of the film at
least touch each other, and optionally overlap; heating at least
part of the polymer film to fuse the polymer film into a polymer
tube; removing the polymer tube from the cylindrical member; and
forming a stent body from the polymer tube.
12. The method of claim 11, wherein the wrapping occurs when the
polymer film is at a temperature not less than the glass transition
temperature of the polymer, and not more than the melting
temperature of the polymer, if there is a melting temperature of at
least 40.degree. C., or not more than the higher of 50.degree. C.
above the glass transition temperature of the polymer and
40.degree. C.
13. The method of claim 11, wherein the wrapping occurs when the
polymer film is at a temperature not less than the glass transition
temperature of the polymer, and not more than 15.degree. C. above
the glass transition temperature of the polymer, or the melting
temperature of the polymer, if the polymer exhibits a melting
temperature, whichever is lower.
14. The method of claim 11, wherein the polymer film is wrapped
around the cylindrical member such that the edges touch each other
but do not overlap, or do not overlap by more than 4 times the film
thickness.
15. The method of claim 11, wherein heating at least a region of
the polymer film comprises heating the edges of the polymer film
and the optional overlapping regions of the polymer film to fuse
the polymer film to form the polymer tube.
16. The method of claim 11, wherein the polymer film is wrapped
around the cylindrical member at least 2 times but not more than
100 times.
17. The method of claim 16, wherein heating at least a region of
the polymer film comprises heating all or substantially all of the
polymer film to fuse the polymer film to form the polymer tube.
18. The method of claim 17, wherein prior to wrapping the polymer
film around the cylindrical member, the polymer film is heated to a
temperature, the temperature being at least the glass transition
temperature of the polymer, and not more than 15.degree. C. above
the glass transition temperature of the polymer, or the melting
temperature of the polymer, if the polymer exhibits a melting
temperature, whichever is lower; wherein after wrapping the polymer
film, the polymer film is maintained at the temperature for a
duration of time, heated to a higher temperature and maintained at
the higher temperature for a second duration of time, or both;
wherein the higher temperature is not greater than the melting
temperature, if there is a melting temperature, or not more than
50.degree. C. above the glass transition temperature of the
polymer, if the polymer does not have melting temperature, or
40.degree. C., if 40.degree. C. is greater than 50.degree. C. above
the glass transition temperature of the polymer; and wherein the
first and second durations of time are at least 2 minutes and not
more than 120 minutes.
19. The method of claim 17, wherein prior to wrapping the polymer
film around the cylindrical member, the polymer film is heated to a
temperature being at least the glass transition temperature of the
polymer, and not more than 15.degree. C. above the glass transition
temperature of the polymer, or the melting temperature of the
polymer, if the polymer exhibits a melting temperature, whichever
is lower; and is maintained at the temperature for a first duration
of time; wherein after wrapping the polymer film, the polymer film
is heated to a higher temperature, and maintained at the higher
temperature for a second duration of time; wherein the higher
temperature is not greater than the melting temperature, if there
is a melting temperature, or at least 50.degree. C. above the glass
transition temperature of the polymer, if the polymer does not have
a melting temperature, or 40.degree. C., if 40.degree. C. is
greater than 50.degree. C. above the glass transition temperature
of the polymer; wherein the first duration of time is at least 10
seconds and not more than 30 minutes; and wherein the second
duration of time is not more than 5 minutes, but at least 5
seconds.
20. The method of claim 11, wherein the polymer film is wrapped
around the cylindrical member at least 1 full time but less than 2
full times.
21. The method of claim 20, wherein heating at least a region of
the polymer film comprises heating at least the overlapping regions
of the polymer film to fuse the polymer film to form the polymer
tube.
Description
BACKGROUND
Field of the Invention
This invention relates to methods of manufacturing polymeric
medical devices, in particular, bioabsorbable medical devices, and
especially stents used in the treatment of blood vessels.
Description of the State of the Art
Until the mid-1980s, the accepted treatment for atherosclerosis,
i.e., narrowing of the coronary artery(ies) was by-pass surgery.
While effective and evolved to a relatively high degree of safety
for such an invasive procedure, by-pass surgery still involves
potentially serious complications, and in the best of cases an
extended recovery period.
With the advent of percutaneous transluminal coronary angioplasty
(PTCA) in 1977, the scene changed dramatically. Using catheter
techniques originally developed for heart exploration, inflatable
balloons were employed to re-open occluded regions in arteries. The
procedure was relatively non-invasive, took a relatively short time
compared to by-pass surgery, and the recovery time was minimal.
However, PTCA brought with it other problems such as vasospasm and
elastic recoil of the stretched arterial wall which could undo much
of what was accomplished and, in addition, it created a new
disease, restenosis, the re-clogging of the treated artery due to
neointimal hyperplasia.
The next improvement, advanced in the mid-1980s, was the use of a
stent to maintain the luminal diameter after PTCA. This for all
intents and purposes put an end to vasospasm and elastic recoil,
but did not entirely resolve the issue of restenosis. That is,
prior to the introduction of stents restenosis occurred in about
30-50% of patients undergoing PTCA. Stenting reduced this to about
15-20%, much improved but still more than desirable.
In 2003, drug-eluting stents or DESs were introduced. The drugs
initially employed with the DES were cytostatic and cytotoxic
compounds, that is, compounds that curtailed the proliferation of
cells that contributed to restenosis. The occurrence of restenosis
was thereby reduced to about 5-7%, a relatively acceptable figure.
Thus, stents made from biostable or non-erodible materials, such as
metals, have become the standard of care for percutaneous coronary
intervention (PCI) as well as in peripheral applications, such as
the superficial femoral artery (SFA), since such stents have been
shown to be capable of preventing early and later recoil and
restenosis.
However, a problem that arose with the advent of DESs was so-called
"late stent thrombosis," the forming of blood clots long after the
stent was in place. It was hypothesized that the formation of blood
clots was most likely due to delayed healing, a side-effect of the
use of cytostatic and cytotoxic drugs. One potential solution is to
make a stent from materials that erode or disintegrate through
exposure to conditions within the body. Thus, erodible portions of
the stent can disappear from the implant region after the treatment
is completed, leaving a healed vessel. Stents fabricated from
biodegradable, bioabsorbable, and/or bioerodable materials such as
polymers can be designed to completely erode only after the
clinical need for them has ended. Like a durable stent, a
biodegradable stent must meet time dependent mechanical
requirements. For example, it must provide patency for a minimum
time period.
Thus, there is a continuing need for stents, particularly
bioabsorbable stents, that meet both mechanical requirements, and
methods of forming such stents.
SUMMARY OF THE INVENTION
Embodiments of the present invention include the following, without
limitation, as described in the following numbered paragraphs:
[0001] A method of making a stent body for supporting a vascular
lumen, including, but not limited to, providing or forming a
polymer solution comprising a solvent and a polymer with an
inherent viscosity of at least 3.3 dl/g, a number average molecular
weight greater than 250,000 g/mole as measured by gel permeation
chromatography using polystyrene standards, or both; and either (a)
immersing a cylindrical member into the polymer solution and
removing the cylindrical member from the polymer solution; wherein
a portion of the polymer solution remains on the surface of the
cylindrical member upon removal from the polymer solution; and
removing at least a portion of the solvent from the polymer
solution remaining on the cylindrical member to form a tubular
layer of the polymer on the cylindrical member; or (b) spraying the
polymer solution onto the cylindrical member; and removing the
solvent during, after, or both during and after the spraying to
form a tubular layer of the polymer on the cylindrical member;
optionally, repeating (a) on one or more occasions, repeating (b)
on one or more occasions, or both, with repeating of the providing
or forming prior to repeating (a), (b), or both, being optional
(because the previous solution may be used for the repetition), to
form a final tubular layer of polymer on the cylindrical member of
a desired thickness; removing residual solvent from the final
tubular layer; and forming a stent body from the final tubular
layer. With respect to the above method, if the optional providing
or forming of the polymer solution is repeated, for each repetition
of the providing or forming, the solvent, the polymer, or both, of
the polymer solution may be different from the polymer, the
solvent, or both used in the prior execution of (a), (b), or both.
In addition, with respect to the above method, removal of the
residual solvent of the polymer solution from the final tubular
layer comprises at least one of the following: removal in a humid
environment of 25% to 100% rh: removal in an environment of solvent
vapor, the solvent being the removal solvent, where the removal
solvent may the same as or different from the solvent of the
polymer solution; removal by exposure to a supercritical fluid;
removal by freeze drying.
[0002] In some embodiments, such as but not limited to that
described in paragraph [0001], a residual solvent level of less
than 2500 ppm (parts per million by weight) is achieved prior to
coating the stent, packaging the stent, or both, or a residual
solvent level of less than 1000 ppm is achieved prior to coating
the stent, packaging the stent, or both.
[0003] In some embodiments, such as but not limited to that
described in paragraph [0001], a residual solvent level of less
than 100 ppm is achieved prior to coating the stent, packaging the
stent, or both, or a residual solvent level of less than 25 ppm is
achieved prior to coating the stent, packaging the stent, or
both.
[0004] In some embodiments, such as but not limited to those
described in paragraphs [0001]-[0003], at least a portion of the
solvent removal occurs during further processing of the final
tubular layer before the formation of the stent from the final
tubular layer, after further processing before the formation of the
stent from the final tubular layer, or both.
[0005] In some embodiments, such as but not limited to those
described in paragraphs [0001]-[0004], at least a portion of the
solvent removal occurs after the formation of the stent from the
final tubular layer.
[0006] In some embodiments, such as but not limited to those
described in paragraphs [0001]-[0005], (a) is executed at least
once and (b) is executed at least once.
[0007] In some embodiments, such as but not limited to those
described in paragraphs [0001]-[0005], (a) is executed at least
once.
[0008] In some embodiments, such as but not limited to those
described in paragraph [0007], (a) is executed at least twice.
[0009] In some embodiments, such as but not limited to those
described in paragraph [0008], (a) is executed at least 5
times.
[0010] In some embodiments, such as but not limited to those
described in paragraphs [0001]-[0005], wherein (b) is executed at
least once.
[0011] In some embodiments, such as but not limited to those
described in paragraph [0010], (b) is executed at least twice.
[0012] In some embodiments, such as but not limited to those
described in paragraph [0011], (b) is executed at least 5
times.
[0013] In some embodiments, such as but not limited to those
described in paragraphs [0001]-[0012], residual solvent removal
comprises removal in a humid environment where the humid
environment is of 25% to 100% relative humidity (rh).
[0014] In some embodiments, such as but not limited to those
described in paragraph [0013], the humid environment is of 40% to
100% rh.
[0015] In some embodiments, such as but not limited to those
described in paragraph [0013], the humid environment is of 65% to
100% rh.
[0016] In some embodiments, such as but not limited to those
described in paragraph [0013], the humid environment is of 80% to
100% rh.
[0017] In some embodiments, such as but not limited to those
described in paragraphs [0013]-[0016], the removal of residual
solvent comprises placing the final tubular layer in the humid
environment for a duration of at least 10 minutes and not more than
1,000 hours.
[0018] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 10 minutes
and not more than 2 hours.
[0019] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 30 minutes
and not more than 4 hours.
[0020] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 1 hour to
and not more than 10 hours.
[0021] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 1 hour and
not more than 12 hours.
[0022] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 2 hours and
not more than 16 hours.
[0023] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 2 hours and
not more than 24 hours.
[0024] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 4 hours and
not more than 48 hours.
[0025] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 12 hours
and not more than 72 hours.
[0026] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 24 hours
and not more than 200 hours.
[0027] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 0.2 hours
and not more than 1,000 hours.
[0028] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 0.5 hours
and not more than 1,000 hours.
[0029] In some embodiments, such as but not limited to those
described in paragraph [0017], the duration is at least 1 hour and
not more than 1,000 hours.
[0030] In some embodiments, such as but not limited to those
described in paragraphs [0013]-[0029], the temperature of the humid
environment, the temperature to which the polymer is heated to and
maintained at in the humid environment, or both, is a temperature
not less than 30.degree. C., but not more than the glass transition
temperature of the polymer if the polymer has a glass transition
temperature of greater than 30.degree. C.
[0031] In some embodiments, such as but not limited to those
described in paragraphs [0013]-[0029], the temperature of the humid
environment, the temperature to which the polymer is heated to and
maintained at in the humid environment, or both, is a temperature
not less than the glass transition temperature of the polymer, or a
temperature of not less than 28.degree. C., if the glass transition
temperature is lower than 25.degree. C., and not more than the
melting temperature of the polymer, if the polymer has a melting
temperature that is not less than 45.degree. C., or not more than
50.degree. C. above the glass transition temperature of the
polymer, if the polymer does not have a melting temperature that is
not less than 45.degree. C., or not more than 45.degree. C., if
50.degree. C. above the glass transition temperature of the polymer
is less than 45.degree. C., the melting temperature is less than
45.degree. C., or both.
[0032] In some embodiments, such as but not limited to those
described in paragraph [0031], the temperature of the humid
environment, the temperature to which the polymer is heated to and
maintained at in the humid environment, or both, is a temperature
of at least 30.degree. C.
[0033] In some embodiments, such as but not limited to those
described in paragraph [0031], the temperature of the humid
environment, the temperature to which the polymer is heated to and
maintained at in the humid environment, or both, is a temperature
of at least 32.degree. C.
[0034] In some embodiments, such as but not limited to those
described in paragraph [0031], the temperature of the humid
environment, the temperature to which the polymer is heated to and
maintained at in the humid environment, or both, is a temperature
of at least 32.degree. C., or at least 10.degree. C. above the
glass transition temperature, whichever is higher, and not more
than 10.degree. C. below the melting temperature, if the polymer
has a melting temperature that is at least 45.degree. C. and is
greater than 10.degree. C. above the glass transition temperature,
or not more than the higher of 40.degree. C. above the glass
transition temperature and 45.degree. C.
[0035] In some embodiments, such as but not limited to those
described in paragraphs [0013]-[0029], provided that the glass
transition temperature is not less than 25.degree. C., the
temperature of the humid environment, the temperature to which the
polymer is heated to and maintained at in the humid environment, or
both, is a temperature between 15.degree. C. above the glass
transition temperature and 15.degree. C. below the melting
temperature, if the polymer has a melting temperature of at least
60.degree. C. and there is more than 30.degree. C. between the
glass transition temperature and the melting temperature, or if the
polymer has no melting temperature of at least 60.degree. C.,
between 10.degree. C. and 45.degree. C. above the glass transition
temperature, or between 15.degree. C. and 40.degree. C. above the
glass transition temperature.
[0036] In some embodiments, such as but not limited to those
described in paragraphs [0013]-[0035], the humid environment is at
a pressure of 760 Torr.+-.100 Torr.
[0037] In some embodiments, such as but not limited to those
described in paragraphs [0013]-[0035], the humid environment is at
a pressure of 760 Torr.+-.50 Torr.
[0038] In some embodiments, such as but not limited to those
described in paragraphs [0013]-[0035], the humid environment is at
a pressure of not more than 380 Torr, but at least 0.001 Torr.
[0039] In some embodiments, such as but not limited to those
described in paragraphs [0013]-[0035], the humid environment is at
a pressure of not more than 200 Torr, but at least 0.001 Torr.
[0040] In some embodiments, such as but not limited to those
described in paragraphs [0013]-[0039], at least a portion of water
absorbed by the polymer is removed from the polymer after the
removal of the residual solvent.
[0041] In some embodiments, such as but not limited to those
described in paragraph [0040], removal of any absorbed water
comprises placing the polymer in an low humidity environment where
the humidity is equal to or less than 40% rh, and at least 0.001%
rh.
[0042] In some embodiments, such as but not limited to those
described in paragraph [0041], the humidity of the low humidity
environment is equal to or less than 30% rh.
[0043] In some embodiments, such as but not limited to those
described in paragraph [0041], the humidity of the low humidity
environment is equal to or less than 20% rh.
[0044] In some embodiments, such as but not limited to those
described in paragraphs [0001]-[0012], residual solvent removal
comprises removal in an environment of removal solvent vapor, where
the removal solvent may the same as or different from the solvent
of the polymer solution.
[0045] In some embodiments, such as but not limited to those
described in paragraph [0044], the removal solvent is different
from the solvent of the polymer solution.
[0046] In some embodiments, such as but not limited to those
described in paragraphs [0044] and [0045], the removal solvent
plasticizes the polymer.
[0047] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0046], the removal solvent has a
boiling point of less than or equal to 80.degree. C.
[0048] In some embodiments, such as but not limited to those
described in paragraph [0047], the removal solvent has a boiling
point of less than or equal to 60.degree. C.
[0049] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0046], the removal solvent is
selected from the group consisting of acetonitrile, methanol,
ethanol, n-propanol, isopropanol, butanol, fluoroform, freons,
methylene chloride (CH.sub.2Cl.sub.2), and chloroform (CHCl.sub.3),
and freons.
[0050] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0048], the removal solvent partial
pressure is at least 100 Torr.
[0051] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0049], the removal solvent partial
pressure is between 30 Torr and 500 Torr.
[0052] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0051], the removal solvent partial
pressure is at least 25% of the value of the pure removal solvent
vapor pressure at the temperature of the environment.
[0053] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0052], the removal solvent partial
pressure is at least 50% of the value of the pure removal solvent
vapor pressure at the temperature of the environment.
[0054] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0053], the removal solvent partial
pressure is at least 75% of the value of the pure removal solvent
vapor pressure at the temperature of the environment.
[0055] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0054], the removal solvent partial
pressure is at least 90% of the value of the pure removal solvent
vapor pressure at the temperature of the environment.
[0056] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0055], the removal of residual
solvent of the polymer solution in an environment of removal
solvent vapor comprises placing the final tubular layer in an
environment of removal solvent vapor for a duration of at least 10
minutes and not more than 1,000 hours.
[0057] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is least 10 minutes and
not more than 2 hours.
[0058] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is at least 30 minutes
and not more than 4 hours.
[0059] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is least 1 hour to and
not more than 10 hours.
[0060] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is at least 1 hour and
not more than 12 hours.
[0061] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is at least 2 hours and
not more than 16 hours.
[0062] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is at least 2 hours and
not more than 24 hours.
[0063] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is at least 4 hours and
not more than 48 hours.
[0064] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is at least 12 hours
and not more than 72 hours.
[0065] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is at least 24 hours
and not more than 200 hours.
[0066] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is at least 0.2 hours
and not more than 1,000 hours.
[0067] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is at least 0.5 hours
and not more than 1,000 hours.
[0068] In some embodiments, such as but not limited to those
described in paragraph [0056], the duration is at least 1 hour and
not more than 1,000 hours.
[0069] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0068], the temperature of the
environment of removal solvent vapor, the temperature to which the
polymer is heated to and maintained at in the environment of
removal solvent vapor, or both, is not less than 30.degree. C. but
not more than the glass transition temperature of the polymer,
provided the polymer has a glass transition temperature of at least
30.degree. C.
[0070] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0068], the temperature of the
environment of removal solvent vapor, the temperature to which the
polymer is heated to and maintained at in the environment of
removal solvent vapor, or both, is not less than the glass
transition temperature of the polymer, or not less than 28.degree.
C., if the glass transition temperature is lower than 25.degree.
C., and not more than the melting temperature of the polymer, if
the polymer has a melting temperature of at least 45.degree. C., or
not more than the higher of 50.degree. C. above the glass
transition temperature of the polymer and 45.degree. C.
[0071] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0068], the temperature of the
environment of removal solvent vapor, the temperature to which the
polymer is heated to and maintained at in the environment of
removal solvent vapor, or both, is not less than 32.degree. C. but
not more than the glass transition temperature of the polymer,
provided the glass transition temperature is at least 32.5.degree.
C.
[0072] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0068], the temperature of the
environment of removal solvent vapor, the temperature to which the
polymer is heated to and maintained at in the environment of
removal solvent vapor, or both, is not less than the glass
transition temperature of the polymer, or not less than 28.degree.
C., if the glass transition temperature is lower than 25.degree.
C., and not more than the melting temperature of the polymer, if
the polymer has a melting temperature of at least 55.degree. C., or
not more than the higher of 60.degree. C. above the glass
transition temperature of the polymer, and 55.degree. C.
[0073] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0072], the temperature of the
environment of removal solvent vapor, the temperature to which the
polymer is heated to and maintained at in the environment of
removal solvent vapor, or both, is at least 30.degree. C.
[0074] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0072], the temperature of the
environment of removal solvent vapor, the temperature to which the
polymer is heated to and maintained at in the environment of
removal solvent vapor, or both, is at least 32.degree. C.
[0075] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0068], the temperature of the
environment of removal solvent vapor, the temperature to which the
polymer is heated to and maintained at in the environment of
removal solvent vapor, or both, is at least 32.degree. C., or at
least 10.degree. C. above the glass transition temperature,
whichever is higher, and not more than 10.degree. C. below the
melting temperature, if the polymer has a melting temperature of at
least 55.degree. C., or not more than the higher of 40.degree. C.
above the glass transition temperature of the polymer, and
45.degree. C.
[0076] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0068], provided that the glass
transition temperature is not less than 25.degree. C., the
temperature of the environment of removal solvent vapor, the
temperature to which the polymer is heated to and maintained at in
the environment of removal solvent vapor, or both, is between
15.degree. C. above the glass transition temperature and 15.degree.
C. below the melting temperature, if the polymer has a melting
temperature of at least 60.degree. C. and there is more than
30.degree. C. between the glass transition temperature and the
melting, or if the polymer has no melting temperature or there is
less than 30.degree. C. between the glass transition temperature
and the melting temperature, between 10.degree. C. and 45.degree.
C. above the glass transition temperature, or between 15.degree. C.
and 40.degree. C. above the glass transition temperature.
[0077] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0076], the environment of removal
solvent vapor is at a pressure of 760 Torr.+-.100 Torr.
[0078] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0076], the environment of removal
solvent vapor is at a pressure of 760 Torr.+-.50 Torr.
[0079] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0076], the environment of removal
solvent vapor is at a pressure of not more than 380 Torr, but at
least 0.001 Torr.
[0080] In some embodiments, such as but not limited to those
described in paragraphs [0044]-[0076], the environment of removal
solvent vapor is at a pressure of not more than 200 Torr, but at
least 0.001 Torr.
[0081] In some embodiments, such as but not limited to those
described in paragraphs [0001]-[0012], removal of residual solvent
from the polymer solution comprises exposure to a supercritical
fluid.
[0082] In some embodiments, such as but not limited to those
described in paragraph [0081], the supercritical fluid is carbon
dioxide, methane, ethane, or ethylene.
[0083] In some embodiments, such as but not limited to those
described in paragraphs [0081] and [0082], the duration of the
supercritical exposure ranged from about 5 minutes to about 120
minutes.
[0084] In some embodiments, such as but not limited to those
described in paragraphs [0001]-[0012], removal of residual solvent
from the polymer solution comprises freeze drying.
[0085] A method of making a stent body for supporting a vascular
lumen, including providing or forming a polymer solution including,
but not excluding other components, a solvent and a polymer with an
inherent viscosity of at least 3.3 dl/g, a number average molecular
weight greater than 250,000 g/mole as measured by gel permeation
chromatography using polystyrene standards, or both; partially or
completely immersing a cylindrical member in the polymer solution
comprising the polymer; wherein the cylindrical member is in a
horizontal position (cylindrical axis parallel to the polymer
solution surface) during at least part of the immersion; removing
the cylindrical member from the solution, wherein a portion of the
polymer solution remains on the surface of the cylindrical member
upon removal from the polymer solution; removing solvent from the
polymer solution remaining on the cylindrical member to form a
tubular layer of the polymer on the cylindrical member; optionally,
repeating the immersion step, removal from the polymer solution
step, and removal of the solvent step on one or more occasions
(where for each repetition the providing or forming the polymer
solution may be optionally repeated) to form a final tubular layer
of polymer on the cylindrical member of a desired thickness; and
forming a stent body from the final tubular layer. With respect to
the method, for the optional repetition of the providing or forming
the polymer solution, the solvent and the polymer of the polymer
solution may each be the same or different from the polymer, the
solvent, or both in the previous polymer solution.
[0086] In some embodiments, such as but not limited to that
described in paragraph [0085], removal of solvent comprises
exposing the cylindrical member to a flow of a heated fluid, where
the fluid may be a gas, a liquid, or a supercritical fluid.
[0087] In some embodiments, such as but not limited to that
described in paragraph [0086], the heated fluid is at a temperature
not less than 30.degree. C. but not more than the glass transition
temperature of the polymer provided the polymer has a glass
transition temperature greater than 30.degree. C.
[0088] In some embodiments, such as but not limited to that
described in paragraph [0086], the polymer has a glass transition
temperature greater than 28.degree. C., the heated fluid is at a
temperature not less than the glass transition temperature of the
polymer, and not more than the melting temperature of the polymer,
if the polymer has a melting temperature not less than 50.degree.
C., or not more than the higher of not more than 50.degree. C.
above the glass transition temperature of the polymer, and
50.degree. C.
[0089] In some embodiments, such as but not limited to that
described in paragraph [0086], the heated fluid is at a temperature
in the range of about 30.degree. C. to about 90.degree. C.
[0090] In some embodiments, such as but not limited to that
described in paragraph [0086], the heated fluid is at a temperature
in the range of about 40.degree. C. to about 90.degree. C.
[0091] In some embodiments, such as but not limited to that
described in paragraph [0086], the heated fluid is at a temperature
in the range of about 50.degree. C. to about 90.degree. C.
[0092] In some embodiments, such as but not limited to those
described in paragraphs [0086]-[0091], the cylindrical member is
rotated during at least part of the time it is exposed to the flow
of the heated fluid.
[0093] In some embodiments, such as but not limited to that
described in paragraphs [0085]-[0092], the cylindrical member is in
a horizontal position or a position that deviates by not more than
5.degree. from the horizontal throughout the immersion and
removal.
[0094] In some embodiments, such as but not limited to that
described in paragraphs [0085]-[0093], the cylindrical member is
totally immersed.
[0095] In some embodiments, such as but not limited to that
described in paragraphs [0085]-[0093], the cylindrical member is
partially immersed.
[0096] In some embodiments, such as but not limited to those
described in paragraph [0095], the method includes, but is not
limited to, partially immersing the cylindrical member into the
polymer solution, and rotating the cylindrical member while
partially immersed.
[0097] In some embodiments, such as but not limited to those
described in paragraph [0096], the cylindrical member is rotated at
least 5.degree. but not more than 360.degree..
[0098] In some embodiments, such as but not limited to those
described in paragraph [0096], the cylindrical member is rotated at
least 5.degree. but not more than 275.degree..
[0099] In some embodiments, such as but not limited to those
described in paragraph [0096], the cylindrical member is rotated at
least 180.degree. but not more than 180.degree..
[0100] In some embodiments, such as but not limited to those
described in paragraph [0096], the cylindrical member is rotated at
least 180.degree. but not more than 360.degree..
[0101] In some embodiments, such as but not limited to those
described in paragraph [0096], the cylindrical member is rotated at
least 360.degree. but not more than 720.degree..
[0102] In some embodiments, such as but not limited to those
described in paragraph [0096], the cylindrical member is rotated at
least two full rotations but not more than 50.
[0103] In some embodiments, such as but not limited to those
described in paragraph [0096], wherein the cylindrical member is
rotated at least two full rotations but not more than 20.
[0104] In some embodiments, such as but not limited to those
described in paragraph [0096], the cylindrical member is rotated at
least two full rotations but not more than 1000.
[0105] A method of making a stent body for supporting a vascular
lumen, comprising coating a web with a polymer solution comprising
a solvent and a polymer, wherein the polymer has an inherent
viscosity greater than 3.3 dl/g, has a weight average molecular
weight greater than 500,000 g/mole, or both; removing at least a
portion of the solvent from the polymer solution remaining on the
web to form a polymer film on the web; separating the polymer film
from the web; and wrapping the polymer film around a cylindrical
member, subject to the constraint that the edges of the film at
least touch each other, and optionally overlap; heating at least
part of the polymer film to fuse the polymer film into a polymer
tube; removing the polymer tube from the cylindrical member; and
forming a stent body from the polymer tube.
[0106] In some embodiments, such as but not limited to that
described in paragraph [0105], the wrapping occurs when the polymer
film is at a temperature not less than the glass transition
temperature of the polymer, or not less than 28.degree. C., if the
glass transition temperature is lower than 25.degree. C., and not
more than the melting temperature of the polymer, if there is a
melting temperature of at least 45.degree. C., or not more than the
higher of 45.degree. C. and 50.degree. C. above the glass
transition temperature of the polymer.
[0107] In some embodiments, such as but not limited to that
described in paragraph [0105], if the polymer has a glass
transition temperature of at least 28.degree. C., the wrapping
occurs when the polymer film is at a temperature not less than the
glass transition temperature of the polymer, and not more than
15.degree. C. above the glass transition temperature of the
polymer, or the melting temperature of the polymer, if the polymer
exhibits a melting temperature, whichever is lower.
[0108] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0107], the polymer film is wrapped
around the cylindrical mandrel such that the edges touch each other
but do not overlap.
[0109] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0107], the polymer film is wrapped
around the cylindrical mandrel such that the edges overlap by not
more than 2%, but at least 0.005% of the surface area of the
film.
[0110] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0107], the polymer film is wrapped
around the cylindrical mandrel such that the edges overlap by not
more than 5%, but at least 0.005% of the surface area of the
film.
[0111] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0107], the polymer film is wrapped
around the cylindrical member such that the edges overlap by not
more than 10%, but at least 0.005% of the surface area of the
film.
[0112] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0112], the polymer film is wrapped
around the cylindrical member such that the edges overlap by not
more than 30%, but at least 0.005% of the surface area of the
film.
[0113] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0107], the polymer film is wrapped
around the cylindrical member at least 1 full time (360.degree.)
but less than 2 full times.
[0115] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0107], the polymer film is wrapped
around the cylindrical member at least 1 full time but not more
than 4.2 full times.
[0116] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0107], the polymer film is wrapped
around the cylindrical member at least 2 times, or at least 4
times, but not more than 100 times.
[0117] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0107], the polymer film is wrapped
around the cylindrical member at least 5 times, but not more than
100 times.
[0118] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0107], the polymer film is wrapped
around the cylindrical member at least 7 times, but not more than
100 times.
[0119] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0107], the polymer film is wrapped
around the cylindrical member at least 10 times, but not more than
100 times.
[0120] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0112], heating at least a region of
the polymer film comprises heating the edges of the polymer film
and the optional overlapping regions of the polymer film to fuse
the polymer film to form the polymer tube.
[0121] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0119], heating at least a region of
the polymer film comprises heating all or substantially all of the
polymer film to fuse the polymer film to form the polymer tube.
[0122] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0121], prior to wrapping the
polymer film around the cylindrical member, the polymer film is
heated to at least the glass transition temperature of the polymer
or at least 28.degree. C., if the glass transition temperature is
lower than 25.degree. C., and not more than the melting temperature
of the polymer, if the polymer exhibits a melting temperature of at
least 40.degree. C., or the higher of 15.degree. C. above the glass
transition temperature of the polymer and 43.degree. C. After
wrapping the polymer film, the polymer film is maintained at the
temperature for a first duration of time, heated to a higher
temperature and maintained at the higher temperature for a second
duration of time, or both. The higher temperature is not greater
than the melting temperature, if there is a melting temperature and
it is at least 60.degree. C., or is not more than the higher of
60.degree. C. above the glass transition temperature of the
polymer, or 60.degree. C. The first and second durations of time
are at least 5 seconds and not more than 120 minutes.
[0123] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0121], prior to wrapping the
polymer film around the cylindrical member, the polymer film is
heated to a first temperature; and after wrapping the polymer film,
the polymer film is maintained at the first temperature for a first
duration of time, heated to a higher temperature and maintained at
the higher temperature for a second duration of time, or both; and
the first and second durations of time are at least 10 seconds and
not more than 120 minutes.
[0124] In some embodiments, such as but not limited to those
described in paragraph [0123], the first duration of time is at
least 10 seconds.
[0125] In some embodiments, such as but not limited to those
described in paragraph [0123], the first duration of time is at
least 30 seconds.
[0126] In some embodiments, such as but not limited to those
described in paragraph [0123], the first duration of time is at
least 60 seconds.
[0127] In some embodiments, such as but not limited to those
described in paragraph [0123], the first duration of time is at
least 2 minutes.
[0128] In some embodiments, such as but not limited to those
described in paragraph [0123], the first duration of time is at
least 5 minutes.
[0129] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0128], the first duration is not
more than 30 minutes.
[0130] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0129], the second duration of time
is at least 10 seconds, and not more than 120 minutes.
[0131] In some embodiments, such as but not limited to those
described in paragraph [0130], the second duration of time is at
least 5 seconds.
[0132] In some embodiments, such as but not limited to those
described in paragraph [0130], the second duration of time is at
least 30 seconds.
[0133] In some embodiments, such as but not limited to those
described in paragraph [0130], the second duration of time is at
least 60 seconds.
[0134] In some embodiments, such as but not limited to those
described in paragraph [0130], the second duration of time is at
least 2 minutes.
[0135] In some embodiments, such as but not limited to those
described in paragraph [0130], the second duration of time is at
least 15 minutes.
[0136] In some embodiments, such as but not limited to those
described in paragraphs [0130]-[0135], wherein the second duration
of time is not more than 60 minutes.
[0137] In some embodiments, such as but not limited to those
described in paragraphs [0130]-[0135], the second duration of time
is not more than 30 minutes.
[0138] In some embodiments, such as but not limited to those
described in paragraphs [0130]-[0135], the second duration of time
is not more than 20 minutes.
[0139] In some embodiments, such as but not limited to those
described in paragraphs [0130]-[0134], the second duration of time
is not more than 10 minutes.
[0140] In some embodiments, such as but not limited to those
described in paragraphs [0130]-[0134], the second duration of time
is not more than 5 minutes.
[0141] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0140], the first temperature is at
least the glass transition temperature of the polymer or at least
28.degree. C., if the glass transition temperature is lower than
25.degree. C., and not more than 60.degree. C. above the glass
transition temperature of the polymer, or not more than the melting
temperature of the polymer, if the polymer exhibits a melting
temperature, or not more than 78.degree. C., whichever of the three
that is above 28.degree. C. is the lowest.
[0142] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0140], the first temperature is at
least the glass transition temperature of the polymer or at least
28.degree. C., if the glass transition temperature is lower than
25.degree. C., and not more than 100.degree. C. above the glass
transition temperature of the polymer, or not more than the melting
temperature of the polymer, if the polymer exhibits a melting
temperature, or not more than 120.degree. C., whichever of the
three above 28.degree. C. is the lowest.
[0143] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0140], the first temperature is at
least the glass transition temperature of the polymer or at least
28.degree. C., if the glass transition temperature is lower than
25.degree. C., and not more than 15.degree. C. above the glass
transition temperature of the polymer, or not more than the melting
temperature of the polymer, if the polymer exhibits a melting
temperature, or not more than 43.degree. C., whichever of the three
above 28.degree. C. is lowest.
[0144] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0140], the first temperature is
between 5.degree. C. and 35.degree. C. above the glass transition
temperature of the polymer, or if the glass transition temperature
is lower than 25.degree. C., than at least 28.degree. C. and not
more than 43.degree. C.
[0145] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0140], the first temperature is
between 5.degree. C. and 35.degree. C. above the glass transition
temperature of the polymer, or if the glass transition temperature
is lower than 25.degree. C., than at least 30.degree. C. and not
more than 43.degree. C.
[0146] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0140], the first temperature is at
least the glass transition temperature of the polymer or 28.degree.
C., if the glass transition temperature is lower than 25.degree.
C., and not more than 15.degree. C. above the glass transition
temperature of the polymer, or not more than the melting
temperature of the polymer, if the polymer exhibits a melting
temperature that is less than 15.degree. C. above the glass
transition temperature of the polymer, or not more than 43.degree.
C., if 15.degree. C. above the glass transition temperature of the
polymer is lower than 43.degree. C.
[0147] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0146], the higher temperature is
the same temperature as or within 5.degree. C. of the first
temperature.
[0148] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0146], the higher temperature is at
least 5.degree. C. above the first temperature, but not greater
than 50.degree. C. above the first temperature.
[0149] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0146], the higher temperature is at
least 10.degree. C. above the first temperature, but not greater
than 40.degree. C. above the first temperature.
[0150] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0146], the higher temperature is at
least 15.degree. C. above the first temperature, but not greater
than 30.degree. C. above the first temperature.
[0151] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0146], if the polymer has a glass
transition temperature that is lower than 25.degree. C., the second
temperature is in the range of 30.degree. C. to 45.degree. C.
[0152] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0146], if the polymer has a melting
that is greater than 25.degree. C., the second temperature is at or
above the melting temperature, but not greater than 100.degree. C.
above the melting temperature.
[0153] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0146], if the polymer has a glass
transition temperature that is greater than 25.degree. C., the
higher temperature is in the range of 25.degree. C. and 75.degree.
C. above the glass transition temperature of the polymer.
[0154] In some embodiments, such as but not limited to those
described in paragraphs [0123]-[0146], the higher temperature is
not greater than the melting temperature, if there is a melting
temperature that is at least 40.degree. C., or not greater than the
higher of not more than 50.degree. C. above the glass transition
temperature of the polymer, and 40.degree. C.
[0155] In some embodiments, such as but not limited to those
described in paragraphs [0105]-[0154], heating at least part of the
polymer film to fuse the polymer film into a polymer tube is
executed at a pressure ranging from 1 psi (50 Torr) to 250 psi
(13,000 Torr).
[0156] A method of making a medical device body, the method
including, but not limited to, grinding a polymer resin into a
smaller particle size under cryogenic conditions; combining the
ground particles with a lubricant which is a non-solvent for the
polymer to form a slurry of the ground particles; forming the
slurry into a partially consolidated device or a partially
consolidated tube; and consolidating the tube or device.
[0157] In some embodiments, such as but not limited to that
described in paragraph [0156], the cryogenic condition is a
temperature of at least -150.degree. C.
[0158] In some embodiments, such as but not limited to that
described in paragraph [0156], the cryogenic condition is a
temperature of at least -196.degree. C. (.+-.0.5.degree. C.) or
lower.
[0159] In some embodiments, such as but not limited to that
described in paragraph [0156], the cryogenic condition is a
temperature of at least -185.9.degree. C. (.+-.0.5.degree. C.) or
lower.
[0160] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0159], the polymer is selected from
the group consisting of poly(L-lactide), a copolymer where one
constituent monomer is L-lactide, poly(glycolide), a copolymer
where one constituent monomer is glycolide, poly(D,L-lactide), a
copolymer where one constituent monomer is D,L-lactide,
polydioxanone, poly(4-hydroxybutyrate), and poly(trimethylene
carbonate), a copolymer where at least one constituent monomer is
polydioxanone, poly(4-hydroxybutyrate), or poly(trimethylene
carbonate), and combinations thereof; and the lubricant is selected
from the group consisting of hydrocarbons or freons.
[0161] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0160], the smaller particle size is
an average particle size of about 0.1 to about 10 microns as
measured by photon correlation spectroscopy, coulter counter, or
light scattering.
[0162] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0160], the smaller particle size is
a number average particle size of about 0.01 to about 30
microns.
[0163] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0160], the smaller particle size is
a number average particle size of about 0.05 to about 25
microns.
[0164] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0160], the smaller particle size is
a number average particle size of about 0.1 to about 10
microns.
[0165] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0164], the slurry comprises 20
weight % to 70 weight % polymer.
[0166] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0165], forming the slurry into a
partially consolidated device or a partially consolidated tube is
performed with the polymer at a temperature not less than the glass
transition temperature of the polymer, or not less than 28.degree.
C., whichever is higher, and not more than 15.degree. C. above the
glass transition temperature of the polymer, or not more than
43.degree. C., whichever is higher.
[0167] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0165], forming the slurry comprises
extrusion.
[0168] In some embodiments, such as but not limited to those
described in paragraph [0157], the extrusion is extrusion of a
tube.
[0169] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0165], forming the slurry comprises
injection molding.
[0170] In some embodiments, such as but not limited to those
described in paragraph [0169], the medical device is a stent formed
by consolidation of injection molded polymer.
[0171] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0169], the consolidation comprises
sintering.
[0172] In some embodiments, such as but not limited to those
described in paragraphs [0156]-[0171], the medical device is a
stent formed from the consolidated tube.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts an exemplary stent.
FIGS. 2A-C depict a dip coating process.
FIG. 3 depicts another dip coating process.
FIG. 4 depicts a method of forming a polymer tube.
DETAILED DESCRIPTION OF THE INVENTION
Use of the term "herein" encompasses the specification, the
abstract, and the claims of the present application.
Use of the singular herein includes the plural and vice versa
unless expressly stated to be otherwise. That is, "a" and "the"
refer to one or more of whatever the word modifies. For example, "a
drug" may refer to one drug, two drugs, etc. Likewise, "the stent"
may refer to one, two or more stents, and "the polymer" may mean
one polymer or a plurality of polymers. By the same token, words
such as, without limitation, "stents" and "polymers" would refer to
one stent or polymer as well as to a plurality of stents or
polymers unless it is expressly stated that such is not
intended.
As used herein, unless specifically defined otherwise, any words of
approximation such as without limitation, "about," "essentially,"
"substantially," and the like mean that the element so modified
need not be exactly what is described but can vary from the
description. The extent to which the description may vary will
depend on how great a change can be instituted and have one of
ordinary skill in the art recognize the modified version as still
having the properties, characteristics and capabilities of the
unmodified word or phrase. With the preceding discussion in mind, a
numerical value herein that is modified by a word of approximation
may vary from the stated value by .+-.15% in some embodiments, by
.+-.10% in some embodiments, by .+-.5% in some embodiments, or in
some embodiments, may be within the 95% confidence interval. As an
example, the term "consisting essentially of" may be 85%-100% in
some embodiments, may be 90%-100% in some embodiments, or may be
95%-100% in some embodiments.
As used herein, any ranges presented are inclusive of the
end-points. For example, "a temperature between 10.degree. C. and
30.degree. C." or "a temperature from 10.degree. C. to 30.degree.
C." includes 10.degree. C. and 30.degree. C., as well as any
temperature in between. In addition, throughout this disclosure,
various aspects of this invention may be presented in a range
format. The description in range format is merely for convenience
and brevity and should not be construed as an inflexible limitation
on the scope of the invention. Accordingly, the description of a
range should be considered to have specifically disclosed all the
possible subranges as well as individual numerical values, both
integers and fractions, within that range. As an example, a
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as
well as individual numbers within that range, for example, 1, 2, 3,
4, 5, and 6. Unless expressly indicated, or from the context
clearly limited to integers, a description of a range such as from
1 to 6 should be considered to have specifically disclosed
subranges 1.5 to 5.5, etc., and individual values such as 3.25,
etc. This applies regardless of the breadth of the range.
A stent or scaffold is a type of medical device, specifically an
implantable medical device. As used herein, an "implantable medical
device" refers to any type of appliance that is totally or partly
introduced, surgically or medically, into a patient's body or by
medical intervention into a natural orifice, and which is intended
to remain there after the procedure. The duration of implantation
may be essentially permanent, i.e., intended to remain in place for
the remaining lifespan of the patient; until the device
biodegrades; or until it is physically removed. Examples of
implantable medical devices include, without limitation,
implantable cardiac pacemakers and defibrillators; leads and
electrodes for the preceding; implantable organ stimulators such as
nerve, bladder, sphincter and diaphragm stimulators, cochlear
implants, prostheses, vascular grafts, self-expandable stents,
stent-expandable stents, stent-grafts, grafts, artificial heart
valves, foramen ovale closure devices, cerebrospinal fluid shunts,
orthopedic fixation devices, and intrauterine devices.
Other medical devices may be referred to as insertable medical
devices that are any type of appliance that is totally or partly
introduced, surgically or medically, into a patient's body or by
medical intervention into a natural orifice, but the device does
not remain in the patient's body after the procedure.
As noted above, a stent is a type of implantable medical device.
Stents are generally cylindrically shaped and function to hold
open, and sometimes expand, a segment of a blood vessel or other
vessel in a patient's body when the vessel is narrowed or closed
due to diseases or disorders including, without limitation, tumors
(in, for example, bile ducts, the esophagus, the trachea/bronchi,
etc.), benign pancreatic disease, coronary artery disease, carotid
artery disease and peripheral arterial disease. A stent can be used
in, without limitation, the cerebral, neuro, carotid, coronary,
pulmonary, aortic renal, biliary, iliac, femoral (superficial
femoral artery) and popliteal vasculature, as well as other
peripheral vasculatures, and in other bodily lumens such as the
urethra, bile duct, or tear duct. A stent can be used in the
treatment or prevention of disorders such as, without limitation,
atherosclerosis, vulnerable plaque, thrombosis, restenosis,
hemorrhage, vascular dissection and perforation, vascular aneurysm,
chronic total occlusion, claudication, anastomotic proliferation,
bile duct obstruction and ureter obstruction.
Another type of medical device is a vascular catheter, which is a
type of insertable device. A vascular catheter is a thin, flexible
tube with a manipulating means at one end, referred to as the
proximal end, which remains outside the patient's body, and an
operative device at or near the other end, called the distal end,
which is inserted into the patient's artery or vein. The catheter
may be introduced into a patient's vasculature at a point remote
from the target site, e.g., into the femoral artery of the leg
where the target is in the vicinity of the heart. The catheter is
steered, assisted by a guide wire than extends through a lumen,
which is a passageway or cavity, in the flexible tube, to the
target site whereupon the guide wire is withdrawn. After the
guidewire is withdrawn, the lumen may be used for the introduction
of fluids, often containing drugs, to the target site. For some
vascular catheters there are multiple lumens allowing for the
passage of fluids without removal of the guidewire. A catheter may
also be used to deliver a stent or may be used to deliver a balloon
used in angioplasty.
As used herein, a "balloon" refers to the well-known in the art
device, usually associated with a vascular catheter, that comprises
a relatively thin, flexible material, forming a tubular membrane,
that when positioned at a particular location in a patient's vessel
may be expanded or inflated to an outside diameter that is
essentially the same as the inside or luminal diameter of the
vessel in which it is placed. In angioplasty procedures, the
balloon is expanded to a size larger than the luminal diameter of
the vessel, as it is a diseased state, and closer to the luminal
size of a healthy reference section of the vessel. In addition to
diameter, a balloon has other dimensions suitable for the vessel in
which it is to be expanded. Balloons may be inflated, without
limitation, using a liquid medium such as water, aqueous contrast
solution, or normal saline solution, that is, saline that is
essentially isotonic with blood.
A "balloon catheter" refers to medical device which is a system of
a catheter with a balloon at the end of the catheter.
A balloon, a catheter, and a stent differ. Stents are typically
delivered to a treatment site by being compressed or crimped onto a
catheter or onto a catheter balloon, and then delivered through
narrow vessels to a treatment site where the stent is deployed.
Deployment involves expanding the stent to a larger diameter,
typically to the diameter of the vessel (or closer to the luminal
size of a healthy reference section of the vessel), once it is at
the treatment site. Stents can be self-expanding or balloon
expandable. The expanded stent is capable of supporting a bodily
lumen for an extended period of time. In contrast, a balloon has a
wall thickness that is so thin that the tubular membrane cannot
support a load at a given diameter unless inflated with a fluid,
such as a liquid or gas. Furthermore, a balloon is a transitory
device that is inserted in the patient's body for only a limited
time for the purpose of performing a specific procedure or
function. Unlike a stent, dilatation balloons are not permanently
implanted within the body. Moreover, vascular catheters have a
length to diameter ratio of at least 50/1.
The structure of a stent is typically a generally cylindrical or
tubular form (but the precise shape may vary from the shape of a
perfect cylinder), and the tube or hollow cylinder may be
perforated with passages that are slots, ovoid, circular, similar
shapes, or any combination thereof. The perforations extend over
the length of the stent, rather than being concentrated in one
region of the stent. In some embodiments, the perforations form at
least 10%, preferably at least 20%, more preferably at least 25%,
and even more preferably at least 30%, but not more than 99% of the
exterior surface area of the tube. A stent may be composed of
scaffolding that includes a pattern or network of interconnecting
structural elements or struts. The scaffolding can be formed from
tubes, or sheets of material, which may be perforated or
unperforated, rolled into a cylindrical shape and welded or
otherwise joined together to form a tube. A pattern may be formed
in the tube by laser cutting, chemical etching, etc.
An example of a stent 100 is depicted in FIG. 1. As noted above, a
stent may be a scaffolding having a pattern or network of
interconnecting structural elements or struts 105, which are
designed to contact the walls of a vessel and to maintain vascular
patency, that is to support the bodily lumen. Struts 105 of stent
100 include luminal faces or surfaces 110 (facing the lumen),
abluminal faces or surfaces 115 (tissue facing), and sidewall faces
or surfaces 120. The pattern of structural elements 105 can take on
a variety of patterns, and the structural pattern of the device can
be of virtually any design. Typical expanded diameters of a stent
range from approximately 1.5 mm to 35 mm, preferably from
approximately 2 mm to 10 mm, and for a coronary stent, from 1.5-6.0
mm. The length to diameter ratio of a stent is typically from 2 to
25. The embodiments disclosed herein are not limited to stents, or
to the stent pattern, illustrated in FIG. 1.
Other types of endoprotheses or stents are those formed of wires,
such as the Wallsten endoprosthesis, U.S. Pat. No. 4,655,771, and
those described in U.S. Pat. No. 7,018,401 B1 and U.S. Pat. No.
8,414,635 B2. Those described in U.S. Pat. No. 7,018,401 B1 and
U.S. Pat. No. 8,414,635 B include, but are not limited to, a
plurality of shape memory wires woven together to form a body
suitable for implantation into an anatomical structure. These
devices may be of a substantially uniform diameter, or may have a
variable diameter such as an hourglass shape. Other stent forms
include helical coils.
The body, scaffolding, or substrate of a stent may be primarily
responsible for providing mechanical support to walls of a bodily
lumen once the stent is deployed therein. The "device body" of a
medical device may be the functional device without a coating or
layer of material different from that of which the device body is
manufactured has been applied. If a device is a multi-layer
structure, the device body may be the layer(s) that form the
functional device, and for a stent this would be the layer(s) which
support the bodily lumen. For a stent, the stent body may be the
scaffolding, for example, as pictured in FIG. 1, without an
exterior coating. If the body is manufactured by a coating process
(typically many layers), the stent body can refer to a state prior
to application of additional coating layers of different material.
"Outer surface" of an implantable device, such as a stent, refers
to any surface however spatially oriented that is in contact, or
may be in contact, with bodily tissue or fluids. As a non-limiting
example, for the stent shown in FIG. 1, the outer surface includes
the abluminal surface, the luminal surface, and the sidewall
surfaces.
Implantable and insertable medical devices can be made of virtually
any material including metals and/or polymers including both
polymers, biostable polymers, and combinations thereof.
Although stents made of nonerodible metals and metal alloys have
become the standard of care for treatment of artery disease, it is
desirable to make stents out of polymers, and especially
biodegradable polymers. Obviously, a stent or other device formed
of a biostable or durable material would remain in the body until
removed. There are certain disadvantages to the presence of a
permanent implant in a vessel such as compliance mismatch between
the stent and vessel and risk of embolic events. The presence of a
stent may affect healing of a diseased blood vessel. To alleviate
such disadvantages, stent can be made from materials that erode or
disintegrate through exposure to conditions within the body. Thus,
erodible portions of the stent can disappear from the implant
region after the treatment is completed, leaving a healed vessel.
Stents fabricated from biodegradable, bioabsorbable, and/or
bioerodable materials such as polymers can be designed to
completely erode only after the clinical need for them has
ended.
Embodiments of the present invention encompass, but are not limited
to, devices that are bioabsorbable. As used herein, the terms
"biodegradable," "bioabsorbable," "bioresorbable," and
"bioerodable" are used interchangeably and refer to materials, such
as but not limited to, polymers, which are capable of being
completely degraded and/or eroded when exposed to bodily fluids
such as blood and can be gradually resorbed, absorbed, and/or
eliminated by the body. The processes of breaking down and
absorption of the polymer can be caused by, for example, hydrolysis
and metabolic processes. Conversely, the term "biostable" refers to
materials that are not biodegradable, or biodegrade over a very
long time period, such as over two or more decades.
The stent must be able to satisfy several mechanical requirements.
The stent must have radial strength and sufficient strength and
rigidity to support the walls of a vessel and withstand radially
compressive forces. Longitudinal flexibility is required for
delivery and deployment. Relatively high toughness or resistance to
fracture is required for the material of the stent must be able to
withstand crimping onto a delivery element, such as the balloon of
a vascular catheter, as well as expansion when deployed. It must
maintain its shape once deployed. For stents used in the
superficial femoral artery (SFA), the mechanical requirements can
be higher than for stents in coronary arteries as the SFA is
subjected to various forces, such as compression, torsion, flexion,
extension, and contraction, which place a high demand on the
mechanical performance of implants. The mechanical requirements on
a stent differ from those of other implantable medical devices such
as catheters, which are not crimped to a smaller size and/or
expanded.
Although biodegradable polymers can de designed to erode away, one
drawback of polymers as compared to metals and metal alloys is that
the strength to weight ratio of polymers is usually smaller than
that of metals. To compensate for this, a polymeric stent can
require significantly thicker struts than a metallic stent, which
results in an undesirably large profile. For example, a typical
thickness for a strut in a metal stent is about 0.003''.
To avoid large struts, polymers may be processed to improve
strength and toughness. The use of polymers of higher molecular
weights may also contribute to strength and toughness of the stent.
The use of high molecular weight polymers may be used instead of,
or in addition to, processing operations to increase polymer
strength.
An example of some of the process operations that may be involved
in fabricating a polymeric stent include, but are not limited to,
the following:
(1) forming a polymeric tube using extrusion or injection molding,
or by rolling and welding a polymer sheet which may be formed by
extrusion, injection molding, solvent casting or another
process;
(2) radially deforming, axially deforming, or both (expanding,
extending, or both expanding and extending) the formed tube by
application of heat and/or pressure;
(3) forming a stent from the deformed tube by cutting a stent
pattern in the deformed tube such as with chemical etching or laser
cutting;
(4) optionally coating the stent with a coating including a
drug;
(5) crimping the stent on a support element, such as a balloon on a
delivery catheter;
(6) packaging the crimped stent/catheter assembly; and
(7) sterilizing the stent assembly.
A noted in step (2), an extruded polymer tube may also be radially
expanded, axially extended, or both radially expanded and axially
extended to increase its radial strength, which can also increase
the radial strength of the stent. The radial expansion process
tends to preferentially align the polymer chains along the radial
or hoop direction which is believed result in enhanced radial
strength. The tube at both the initial and expanded diameter have
wall thicknesses that are large enough that they can support an
inward radial force or load. The radial expansion and axial
extension may occur sequentially with either the radial expansion
and the axial extension occurring first in time, and there may be a
15 second to 3 hour delay between the two operations. The radial
expansion and axial extension may occur concurrently, where at
least 50% of time, at least 70% of the time, or at least 90% of the
time that the tube is being expanded, the tube is also being
extended, or vice versa.
During the expansion step, the tube is heated to a temperature
between glass transition temperature (T.sub.g) (if the polymer has
a glass transition temperature greater than about 25.degree. C.),
and the melting point of the polymer, if the polymer exhibits a
melting point, and the tube is expanded to an expanded diameter.
Upon expansion the tube is cooled to below the Tg of the polymer,
typically to ambient temperature (20.degree. C. to 30.degree. C.),
to maintain the tube at an expanded diameter. The percent radial
expansion may be between about 50% and 600%, preferably 300% to
500%, or any specific value within either of these ranges, such as
about 400%. The percent radial expansion is defined as RE %=(RE
ratio-1).times.100%, where the RE Ratio=(Inside Diameter of
Expanded Tube)/(Original Inside Diameter of the Tube). The percent
axial extension expansion may be between about 10% and about 200%,
preferably between about 15% and about 120%, or any specific value
within either of these ranges, such as about 20%. The percent of
axial extension that the polymer tube undergoes is defined as AE
%=(AE ratio-1).times.100%, where the AE Ratio=(Length of Extended
Tube)/(Original Length of the Tube). The expansion of the tube
decreases the wall thickness from about 300 to 600 microns
(microns=micrometers, 10.sup.-6 meters) to a thickness in the range
about 70 to about 200 microns. The width and thickness of the
struts of the stent can be, for example, between 90-160
microns.
After cutting a stent pattern into the expanded tube, as noted in
step (4) the stent scaffolding may then be optionally coated with a
coating which can include a polymer and a drug. The drugs may be
distributed uniformly or non-uniformly in a coating that is
disposed over all of, substantially all of, or at least a portion
of, the outer surface of the device.
In order to make the stent ready for delivery, the stent is secured
to a delivery element such as a delivery balloon. In this process,
the stent is compressed to a reduced diameter or crimped over the
balloon. During crimping and in the crimped state, some sections of
the stent are subjected to high, localized stress and strain. Due
to the fact that some regions of the stent structure are subjected
to high compressive stress and strain, the stent during crimping
and in the crimped state may be susceptible to cracking.
The stent is deployed by expanding it to an increased diameter at
an implant site in a vessel which can be greater than the as-cut
diameter of the stent. The deployed stent must have sufficient
radial strength to apply an outward radial force to support the
vessel at an increased diameter for a period of time.
Some of the methods used to form a stent or methods of forming a
polymer tube or a polymer construct from which a stent is formed
involve processing at high temperatures, such as at and/or above
the melting point of the polymer. In addition, methods such as
extrusion subject the polymer to high shear stresses. The exposure
to high shear, to high temperatures, or both, may result in
degradation of the polymer. The degradation may reduce the
molecular weight of the polymer, and thus, potentially reduce the
strength of the polymer. For higher molecular weight polymers,
higher temperatures are needed to obtain a viscosity sufficiently
low for processing, which may lead to even more degradation which
may reduce the molecular weight.
As used herein, "polymer construct" refers to any useful article of
manufacture made of a polymer. A polymer construct may be further
processed to form a medical device. Some examples of polymer
constructs include, but are not limited to, a tube, a sheet, a
fiber, etc.
Various embodiments of the present invention encompass methods of
forming a medical device, such as a stent, having a device body or
scaffolding formed or fabricated from a polymer. The various
embodiments of the present invention encompass methods of solvent
or other processing of the polymer such that the polymer is
processed at a lower temperature, and with lower exposure to shear
stress.
Although the discussion that follows may make reference to a stent
or stents as the medical device, the embodiments of the present
invention are not so limited, and encompass any medical device
which may benefit from the embodiments of the invention. Examples
of the other types of medical devices which may benefit from the
embodiments of the present invention, include, without limitation,
extravascular wraps, intrapulmonary or intra-urethral stents,
stents for other than vascular lumens, drug delivery devices
including implantable drug delivery devices, and any substrate that
may be used to support a surgical procedure, such as and without
limitation, a device used to support an anastomotic site via
minimally invasive bypass surgery. As used herein, "polymeric
stent" refers to a stent having a scaffolding (or body) that is
made completely, or substantially completely, from a polymer, or
the scaffolding is made from a composition including a polymer and
a material. If the scaffolding is made from a composition including
a polymer and a material, the polymer is a continuous phase of the
scaffolding, the scaffolding is at least 50% by weight polymer, or
the scaffolding is at least 50% by volume polymer. In some
embodiments, a polymeric stent may have a scaffolding made from a
composition including a polymer and a material that is at least
70%, at least 80%, at least 90%, or at least 95% by volume or by
weight polymer, but not more than 99.5% by volume or by weight.
Analogous definitions apply to a polymeric tube, a polymer
construct, or a polymeric medical device except that the reference
to the scaffolding would be replaced by "tube" for a polymer tube,
"construct" for a polymer construct, and "device body" for a
medical device. In some embodiments, the polymeric scaffolding,
polymeric construct, polymer tube, or polymeric device, is free of
drugs, or essentially free of drugs (not more than 0.01 weight %,
or not more than 0.001 weight % drug).
Some processes, such as melt extrusion and radiation sterilization,
result in a decrease in the molecular weight of the polymer. Thus,
in some embodiments, the formation of a polymer construct, such as
a tube, from which the device, such as a stent, is formed using
solvent processing methods. Solvent processing generally refers to
forming a polymer construct such as a tube from a mixture of a
polymer and a solvent. Non-limiting examples of solvent processing
methods include spray coating, gel extrusion, supercritical fluid
extrusion, roll coating and dip coating. In some embodiments, the
polymer construct, such as a tube, is formed by ram extrusion,
compression molding, or both, which may result in less polymer
degradation than traditional melt processing operations.
Solvent processing methods include the use of gel extrusion, as
described in patent application Ser. No. 11/345,073 (United States
Patent Application Publication No. 2007-0179219 A1, published on
Aug. 2, 2007), which is incorporated by reference herein in its
entirety.
Another preferred solvent processing method is dip coating. Dip
coating is a method of forming a material layer on an object which
includes immersing the object in a solution of a material, which is
this case is a polymer, where the polymer (and optionally another
material) may be dissolved, partially dissolved, dispersed, or a
combination thereof, in a solvent, withdrawing the object from the
solution, and removing solvent from the solution retained on the
surface of the object. In preferred embodiments, the polymer is
dissolved in the solvent. As used herein, with reference to a
polymer solution for forming a polymer construct by dipping,
spraying, or gel extrusion, a "solvent" is defined as a substance
that dissolves one or more substances, partially dissolving the
substance(s), disperses the substance(s), or a combination thereof,
to form a uniformly dispersed solution at a selected temperature
and pressure. A solvent can refer to one chemical compound, or a
mixture of chemical compounds. A solvent can be a fluid. Upon
removal of the solvent, a layer of polymer is formed on the surface
of the object. The steps above can be repeated to form multiple
layers of polymer (optionally including another material) over the
object to obtain a desired thickness of a polymer tube on the
object.
The object can be a cylindrical member or mandrel over which a
polymer tube is formed. The mandrel can be made of any material
that is not soluble in the solvent of the polymer solution. In some
embodiments, the mandrel is made of a metal such as aluminum or
stainless steel. In other embodiments, the mandrel is made from a
glass with a polished surface. In some other embodiments, the
mandrel is made of a soluble material that is insoluble in the
solvent used for the coating. In other embodiments, the mandrel is
made of a polymer. The polymer tube may be formed so that its
radial thickness or the thickness of the wall of the polymer tube
is the desired thickness of a stent scaffolding. The polymer tube
may then be removed from the mandrel and machined to form a stent
scaffolding.
FIGS. 2A-C illustrate a dipping or dip coating process. As shown in
FIG. 2A, a mandrel 202 is lowered, as shown by an arrow 206 into a
container 204 having a polymer solution 200 that includes a
polymer, and optionally including an additive dissolved, dispersed,
or both dissolved and dispersed in the solution. As shown in FIG.
2B, at least part of the mandrel remains immersed in solution 200
for a selected time or dwell time. In some embodiments, the mandrel
is only partially immersed in the solution. Referring to FIG. 2C,
mandrel 202 is then removed from solution 200 as shown by an arrow
212. Solution 210 is retained on mandrel 202 after removal from the
solution 200 in container 204. Solvent is then removed from the
retained solution 210 which results in the formation of a tubular
layer of the polymer, and optionally any additives or other
materials also included in the solution. The dipping and drying is
optionally repeated one or many times.
Between dips, the solvent can be removed using various types of
drying methods. The solvent can be removed from the solution
retained on the mandrel by methods known in the art including air
drying, baking in an oven, or both. As used herein, "removing the
solvent" or "solvent is removed" includes allowing the solvent to
evaporate, as well as use of other means to increase the rate of
solvent evaporation. In air drying a gas stream is directed on or
blown onto the mandrel. The gas can be at room temperature (about
20.degree. C. to about 25.degree. C.) or heated (a temperature in
the range of about 30.degree. C. to about 90.degree. C.) to
increase the removal rate. In some embodiments, drying is done at
reduced pressure such as less than 200 Torr, or less than 100 Torr,
but at least 0.001 Torr.
For the method described above, as shown in FIG. 2A, the
cylindrical axis of the mandrel is perpendicular to the surface of
the solution, although the mandrel can be immersed at an angle
different from 90.degree. to the solution surface. Similarly, as
shown in FIG. 2C, the cylindrical axis of mandrel 202 is
perpendicular to the surface of the solution when removed, although
the mandrel can be removed at angle different from 90.degree. to
the solution surface. The use of a 90.degree. angle is expected to
facilitate uniformity in the polymer tube thickness. In some
embodiments, the mandrel is dipped, removed, or both, horizontally,
that is at an angle that is parallel to the surface of the solution
(0.degree.), with a variation of up to .+-.5.degree.,
.+-.10.degree., or .+-.15.degree. from perfectly parallel. In some
embodiments, the mandrel is dipped, removed, or both, at an angle
that is between parallel (0.degree.) and perpendicular
(90.degree.), such as, without limitation, between 20.degree. and
70.degree., or about 45.degree.. In some embodiments, the
cylindrical axis of the mandrel is parallel with the surface of the
solution upon immersion and removal, and between dips the mandrel
is rotated at least 360.degree. about its cylindrical axis, but not
more than 100 complete rotations (1 complete rotation is
360.degree.).
Other dipping processes can be envisioned by those skilled in the
art. These include immersing only a small part of the mandrel into
the solution and while rotating parallel to the solution. This
process helps ensure an even polymer tube thickness. A non-limiting
example is shown in FIG. 3 where a mandrel 84 is attached to a
support assembly 112, positioned so that only the part of the outer
surface of the mandrel 84 is in contact with, or partially immersed
in the surface of the polymer solution 30 as disposed in reservoir
64. The support assembly 112 rotates the mandrel 84 such that only
part of the surface is in contact or immersed in the polymer
solution. As shown in FIG. 3, the mandrel is parallel to the
surface of the solution, and may vary by .+-.5.degree.,
.+-.10.degree., or .+-.15.degree. from perfectly parallel. The
cylinder while partially immersed may be rotated only part of a
rotation (at least 5.degree. but not more than 360.degree.), such
as between 5.degree. and 275.degree., between 5.degree. and
180.degree., or between 180.degree. and 360.degree.. In some
embodiments, the mandrel is rotated more than one complete
rotation, such as between 360.degree. to 720.degree., or in some
embodiments, more than 2 complete rotations, but not to exceed 1000
complete rotations. In some embodiments, the mandrel may be
periodically removed from the solution entirely (raised), and
rotated one or more times (at least one complete rotation, not to
exceed 1000) to remove at least a portion of the solvent. The
mandrel may be then again be positioned such that only part of the
surface is in contact with or immersed in the polymer solution, and
following the positioning, rotation of the mandrel, and
subsequently followed by removal and rotation, etc. The immersion
into the solution and rotation followed by removal with optional
rotation as described above may be repeated on one or more
occasions (in some embodiments, the sequence of removal and
rotation followed by removal from the solution and rotation is
repeated at least twice).
In another embodiment, a hollow mandrel is dipped into the solution
of the polymer, optionally including an additive, and a vacuum is
drawn at one end of the mandrel causing the solution to be drawn
into the mandrel. When the mandrel is lifted from the solution, the
solution will drain from the inside leaving the inside to the
mandrel coated with the polymer forming a polymer tube.
There are several parameters in the dipping process that can affect
the quality and uniformity of the polymer tube, typically built of
multiple layers of polymer. It is desirable for the polymer tube to
be uniform circumferentially and along the cylindrical axis.
Parameters include the concentration and viscosity of the polymer
solution, the dwell time in solution, and the rate of removal of
the mandrel from solution.
In some embodiments, polymer concentration can be at or near
(within 10%) a saturation concentration. Such concentration is
expected to result in the highest viscosity and the thickest
polymer layer per immersion. In some embodiments, the polymer
concentration may be limited to a viscosity of not more than 10,000
centiPoise (cP), and preferably, not more than 7,500 cP, but at a
viscosity of at least the pure solvent. Alternatively, polymer
concentration can be less than saturation, for example, less than
50% or less than 25% saturation. A more dilute and less viscous
solution may result in a more uniform polymer layer. However, a
more dilute solution will require a higher number of repeated
dipping steps to provide a final desired polymer tube
thickness.
The dip coating process allows for use of a different solution for
one or more dips allowing some solutions to include drugs,
radiopaque agents, or other additives, in addition to or instead of
the polymer. Thus, there may be concentration gradients of an
additive, such as a drug, across the thickness of the tube, and the
device formed from such a polymer tube.
There are various ways to remove the polymer tube from the mandrel
to further process the polymer tube in the fabrication of a stent.
Methods include using a dissolvable material as a coating on the
mandrel, and dissolving it after the tube is the proper thickness.
As a non-limiting example, the mandrel is a wax and the coating
polymer is PLLA. If a hollow mandrel is used and the polymer forms
a seal over one end, then compressed air blow into the other open
end forces the tube off the mandrel. In some embodiments, the
"mandrel" is an inflated tubular balloon which is deflated after
the dip coating and solvent removal is complete (or solvent removal
is complete to about 10 weight % or less). Other methods include
the use of a solvent to swell the polymer or a greasy or oily
coating on the mandrel either of which allows the polymer tube to
be slipped off the mandrel. Heating or cooling of the polymer tube,
the mandrel, or both may be used to assist in the removal of the
tube. In some embodiments, a mandrel made of
poly(tetrafluoroethylene),
poly(tetrafluoroethylene-co-hexafluoropropylene), Kel-F.RTM.
poly(chlorotrifluoroethylene), poly(vinylidene fluoride),
poly(vinylidene fluoride-co-chlorotrifluoroethylene, or other
fluoropolymer is used.
In some embodiments, instead of, or in addition to, dipping, the
polymer solution may be sprayed onto a mandrel. Spray coating is
another solvent processing method which may be used to form a tube
or other construct, and is described in United States Patent
Application Publication No. 2010-0262224 A1, published on Oct. 14,
2010, which is incorporated by reference herein in its
entirety.
Embodiments of the spraying method may include an operation
including spraying the polymer solution over the mandrel, and then
drying the mandrel to substantially remove the solvent (at least 80
weight %, at least 90 weight %, at least 95 weight %, or at least
98 weight % of the solvent in the solution is removed during the
spraying process, drying between spraying process, or both
processes). The procedure of spraying and drying may be optionally
repeated one or more time until a desired thickness of polymer has
been deposited onto the mandrel. In preferred embodiments, the
polymer solution is atomized through pressure or ultrasound, and
the spraying operation may use an external gas assisted atomizer,
an internal gas assisted atomizer, a nebulizer, a rotating disc
sprayer, or an ultrasonic sprayer. During the spraying process,
relative to the sprayer or applicator, the mandrel may be rotated,
translated, or both.
Dipping and spraying operations may both be used to form a polymer
tube or a polymer construct. As a non-limiting example, several
tubular polymer layers may be applied to a mandrel or other
cylindrical member by dipping, followed by application of more
tubular polymer layers by spraying, and optionally following by
dipping and spraying on one or more occasions to form one or more
additional tubular polymer layers.
In preferred embodiments, a polymer tube is formed of
poly(L-lactide) or a polymer in which at least one constituent
monomer is L-lactide, preferably at least 50 mol % L-lactide, by a
solvent processing operation, the operation being a dipping
operation, a spraying operation, or a combination thereof. The
solvent for the polymer solution for the solvent processing
operation may be methylene chloride, chloroform, acetone,
2-butanone, cyclohexanone, tetrahydrofuran, dioxane, 1,1,1,
trichloroethane, trichloroethylene, and combinations thereof.
Another method of forming a tubular medical device, such as a
stent, is to roll a sheet in to the shape of a tube and join the
edges together such as by, without limitation, welding, heat
sealing, use of an adhesive, or a combination thereof. Roll coating
of a web or other means of solvent casting followed by drying to
form a film is well known in the art. In some embodiments of the
present invention, the web may act as a release layer, allowing the
film to be separated from the web. The web should be reasonably
stiff to prevent stretching of the web during application of a
polymer solution (in which the polymer, and optionally another
material, may be dissolved, partially dissolved, dispersed, or a
combination thereof in the solvent). As used herein, with reference
to a solvent used in a polymer solution for a web coating
operation, a "solvent" is defined as a substance that dissolves one
or more substances, partially dissolving the substance(s),
disperses the substance(s), or a combination thereof, to form a
uniformly dispersed solution at a selected temperature and
pressure. A solvent can refer to one chemical compound, or a
mixture of chemical compounds. A solvent can be a fluid. With
respect to web coating, the solvent can be removed from the
solution retained on the web by methods known in the art including
air drying, baking in an oven, or both. In air drying a gas stream
is directed on or blown onto the web. The gas can be at room
temperature (about 20.degree. C. to about 25.degree. C.) or heated
(a temperature in the range of about 30.degree. C. to about
90.degree. C.) to increase the removal rate. In some embodiments,
drying is done at reduced pressure such as less than 200 Torr, or
less than 100 Torr, but at least 0.001 Torr.
In some embodiments, solvent may be removed to a level such as less
than 2 weight %, less than 1 weight %, less than 0.5 weight %, less
than 0.2%, or less than 0.1 weight % solvent in the polymer film
before the film is removed from the web. In other embodiments,
solvent may be removed to a level such as 2 weight % to 12 weight %
solvent in the polymer film before the film is removed from the
web.
In a production line, the solution would be cast or rolled onto a
web or substrate which is on rollers and may subsequently move
through an oven or a heated section.
As the polymer film is separated from the web it may be wrapped
around a cylindrical member such as a mandrel, or roller. In some
embodiments, the film edges just touch each other, and in other
embodiments, there is some overlap where one edge of the film at
least partially covers the other edge of the film already wrapped
around the mandrel. In some embodiments, the overlap is not more
than 2%, not more than 5%, or not more than 10% of the surface area
of the film, but at least 0.005%. In some embodiments, more than
30% of the surface area overlaps. In some embodiments, the polymer
film is wrapped around the cylindrical member at least 1 complete
time, but less than 2 complete times. In some embodiments, the
polymer film is wrapped around the cylindrical member at least 2
times, at least 5 times, at least 7 times, or at least 10 times,
but not more than 100 times. In some embodiments, the polymer film
is wrapped around the cylindrical member not more than 4 complete
times, or the polymer tube thickness is not more than 4 times the
thickness of the polymer film. The number of times that the film is
wrapped entirely around the mandrel depends upon the thickness of
the film, and the desired thickness of the final tube. The final
formed polymer tube may be of the same thickness of the final
device, or may be thicker if the tube will be subject to further
processing that may reduce the wall thickness, such as, and without
limitation, radial expansion.
In some embodiments, the wrapping may be executed at room
temperature (about 20.degree. C. to about 25.degree. C.), or when
the polymer is at its glass transition temperature (.+-.3.degree.
C.), or at a temperature that is not less than the glass transition
temperature of the polymer (or at least 28.degree. C., if the glass
transition temperature is lower than 25.degree. C.), and not more
than the melting temperature of the polymer, if the polymer has a
melting temperature, or if the polymer does not have melting
temperature, not more than 50.degree. C. above the glass transition
temperature of the polymer or not more 40.degree. C., whichever of
the three is higher. If the polymer exhibits more than one glass
transition temperature, then the heating may be above the highest,
above the lowest, or above the or an intermediate glass transition
temperature (if one or more exist), and one of skill in the art
will be able to determine the appropriate glass transition
temperature if more than one exists based on the objective of
having the polymer film be sufficiently pliable to wrap around the
cylindrical member or mandrel. In some embodiments, the wrapping
occurs when the polymer film is at a temperature not less than the
glass transition temperature of the polymer, and not more than
15.degree. C. above the glass transition temperature of the
polymer, or if the polymer exhibits a melting temperature and the
melting temperature of the polymer is less than 15.degree. C. above
the glass transition temperature of the polymer, the melting
temperature of the polymer. Typically, the polymer film may be
heated to the target temperature prior to the beginning of the
wrapping operation, and may be maintained at the temperature for at
least the duration of the wrapping operation.
The tube may be formed from the wrapped polymer film by joining or
sealing the edges if only the edges touch. The edges may be sealed
by heating the edges and pressing the edges together to form a
seal. The heating may be above the glass transition temperature of
the polymer, such as between 5.degree. C. and 35.degree. C. above
the glass transition temperature, or if the glass transition
temperature is lower than 25.degree. C., than at least 28.degree.
C., and preferably at least 30.degree. C., and not more than the
melting temperature of the polymer, if the polymer has a melting
temperature, or if the polymer does not have melting temperature,
not more than 60.degree. C. or not more than 100.degree. C. above
the glass transition temperature of the polymer, whichever is
higher. If the polymer exhibits more than one glass transition
temperature, then the heating may be above the highest, above the
lowest, or above an intermediate glass transition temperature. One
of skill in the art will be able to determine the appropriate glass
transition temperature if more than one exists based on the
objective sealing the edges together to form a polymer tube. If the
polymer also exhibits one or more melting temperatures, the heating
may be above the or any of the melting temperatures of the polymer,
and one of skill in the art can select the appropriate melting
temperature if more than one exists. In some embodiments, only the
polymer at or near the edges is heated. In other words, the entire
polymer film may not be heated to a higher temperature. However, in
some embodiments, the entire polymer film is heated.
Alternatively or additionally, an adhesive may be placed at one or
both of the edges. In some embodiments, a solvent may be added to
the edges to swell the polymer along the edge with the result being
a "solvent" weld resulting from some of the polymer chains at the
edges becoming entangled with polymer chains from the other edge.
The use of the solvent may be combined with heating of the polymer,
the use of an adhesive, or both.
Similar methods may be used if the polymer film overlaps except
that the seal may be over the entire overlap region. If multiple
layers are wrapped around the mandrel, the polymer film may be
fused or sealed by heating the polymer, and optionally applying
pressure to the polymer. The temperature to which the polymer is
heated may be between the glass transition temperature of the
polymer (or at least 28.degree. C. if the glass transition
temperature is lower than 25.degree. C., preferably at least
30.degree. C., and in some embodiments, at least 32.degree. C.),
and the melting temperature, if the polymer exhibits a melting
temperature of at least 60.degree. C., or if the polymer does not
exhibit a melting temperature, a temperature that is not more than
60.degree. C., or not more than 100.degree. C. above the glass
transition temperature, whichever is higher. In some embodiments,
if the polymer has a melting temperature, the fusing is executed by
heating the polymer to at, or above, such as within 25.degree. C.
of, the melting temperature. Similar to the situation with the
wrapping, if the polymer exhibits more than one glass transition
temperature, then the heating may be above the highest, above the
lowest, or above an intermediate glass transition temperature, and
one of skill in the art will be able to determine the appropriate
glass transition temperature if more than one exists based on the
objective of the objective of fusing the polymer film to form a
tube. Similarly, if the polymer has more than one melting point,
the upper limit of the temperature range for fusing the polymer
film may be the lowest, the highest, or an intermediate melting
point.
In some embodiments, the temperature to which the polymer film is
heated to fuse the polymer film into a tube may be the same
temperature as or within 5.degree. C. of the temperature of the
wrapping operation. In some embodiments, the temperature for fusing
the film together to form a tube may be above, such as at least
5.degree. C. above but not more than 50.degree. C. above, the
temperature of the polymer film during the wrapping operation. As a
non-limiting example, for a polymer with a glass transition
temperature not lower than 25.degree. C., the wrapping may be
executed with the polymer at a temperature between the glass
transition temperature, and 15.degree. C. above the glass
transition temperature, and the subsequent fusing executed after
the polymer film is heated to (and maintained at) a higher
temperature, but not in excess of the melting temperature, or if
the polymer does not have a melting temperature, not more than
50.degree. C., such as a temperature between 25.degree. C. and
45.degree. C. above the glass transition temperature. For those
polymers that have a glass transition temperature is lower than
25.degree. C., the wrapping may be done at room temperature, and
the fusing at a temperature in the range of 30.degree. C. to
45.degree. C., or at or above the melting temperature, if the
polymer has a melting temperature that is greater than 25.degree.
C.
In some embodiments, the wrapping may be executed with the polymer
at a temperature between 5.degree. C. and 15.degree. C. above the
glass transition temperature (for a polymer with a transition
temperature is equal to or greater than 25.degree. C.), and the
subsequent fusing executed after the polymer film is heated to (and
maintained at) a higher temperature, such as between 25.degree. C.
and 75.degree. C. above the glass transition temperature. In some
embodiments, the temperature for fusing the film together to form a
tube may be at least 10.degree. C. above, but not greater than
40.degree. C. above, or at least 15.degree. C. above, but not
greater than 30.degree. C. above, the temperature of the polymer
film during the wrapping operation.
In some embodiments, the tube is maintained at the temperature of
the wrapping operation after the wrapping is complete for a
duration of time ranging from at least 10 seconds, at least 10
seconds, at least 30 seconds, at least 60 seconds, at least 2
minutes, or at least 5 minutes, and not more than 120 minutes, then
the polymer film is heated to a higher temperature for the fusing
operation. In some embodiments, the tube is maintained at the
temperature of the wrapping operation after the wrapping is
complete for not more than 30 minutes. After the polymer is heated
to the higher temperature for the fusing operation, the polymer may
be maintained at the higher temperature for a duration ranging from
at least 5 seconds, at least 30 seconds, at least 60 seconds, or at
least 2 minutes, but not more than 5 minutes, not more than 10
minutes, not more than 20 minutes, or not more 60 minutes. In some
embodiments, the duration of the fusing operation is between 15
minutes and 30 minutes.
The fusing operation may be carried out under pressure. The
pressure may range from 1 psi (50 Torr) to 250 psi (13,000
Torr).
In some embodiments, an adhesive, a solvent, or both, may be used
in conjunction with heat, pressure, or both. A thin layer of an
adhesive may be applied to one side of the film before or after the
film is removed from the web. A solvent which at least partially
swells the polymer (at least 1 weight % absorption of solvent) may
be applied to one side of the film before, or during the wrapping
of the film. As a non-limiting example, solvent may be sprayed onto
film about to be wrapped on the mandrel as shown in FIG. 4. In some
embodiments, the solvent is only partially removed from the polymer
film so that the residual solvent acts as a plasticizer. The
residual solvent, particularly if it swells the polymer, may
enhance fusion between the layers. In some embodiments, the
residual solvent is present at a level of 2 weight % to 10 weight %
of the polymer, or 5 weight % to 10 weight % of the polymer
film.
Another method of processing a polymer that limits or avoids high
temperatures and high shear stresses is to use cryogrinding to form
small particles of the polymer resin which are subsequently formed
into a construct or device. Cryogrinding is a process in which a
material is cooled (typically with liquid nitrogen or liquid
argon), and then after cooling, ground or milled into smaller size
particles. Cryogrinding is particularly useful for polymers with a
glass transition temperature below 25.degree. C. Cryogrinding may
reduce the particle size to a number average particle size of in
the range of about 0.01 to about 30 microns, preferably in the
range of about 0.05 to about 25 microns, and more preferably in the
range of about 0.1 to about 10 microns. In some embodiments, the
cryoground particles may be utilized in a 3-dimensional "printing"
apparatus which is well-known in the art. In some embodiments, the
polymer particles may be combined with a fluid (a gas, a liquid, or
a supercritical fluid), typically a liquid, which is a non-solvent
for the polymer to form a slurry of the polymer in the fluid. The
non-solvent may be referred to as a lubricant. The concentration of
polymer in the slurry may be from 20 weight % to 70 weight %. As
used herein, a "non-solvent" of a polymer is a fluid which
dissolves not more than 0.1% of the polymer. The fluid may act as a
lubricant to allow processing of the slurry by methods such as
extrusion of an unconsolidated tube, or injection molding of an
unconsolidated tube or device. The extrusion or injection molding
may occur at a temperature in the range of 0 to 25.degree. C. below
the melting temperature of the polymer (or 0 to 50.degree. C. above
the glass transition temperature, provided it is equal to or
greater than 25.degree. C., if the polymer has no melting
temperature), and not more than 10.degree. C. above the melting
temperature of the polymer (or 10.degree. C. 0 to 75.degree. C.
above the glass transition temperature if the polymer has no
melting temperature). The non-solvent may be removed (at least 95
weight % or at least 98 weight %) during the extrusion or injection
molding process.
As a non-limiting example, the polymer which is cryoground is
selected from the group of poly(L-lactide), a copolymer where one
constituent monomer is L-lactide, poly(glycolide), a copolymer
where one constituent monomer is glycolide, poly(D,L-lactide), a
copolymer where the constituent monomers include D-lactide,
L-lactide, and at least one member of the group consisting of
polydioxanone, poly(4-hydroxybutyrate), and poly(trimethylene
carbonate), a copolymer where one constituent monomer is
D,L-lactide, polydioxanone, poly(4-hydroxybutyrate), or
poly(trimethylene carbonate), a copolymer where at least one
constituent monomer is polydioxanone, poly(4-hydroxybutyrate), or
poly(trimethylene carbonate), and combinations thereof, and wherein
the lubricant (non-solvent) is selected from the group consisting
of hydrocarbons, oils or freons.
The unconsolidated tube or unconsolidated device is consolidated by
"sintering," or another process. Sintering is a process in which
particles are formed into a solid mass by application of heat and
pressure but without melting the material. The sintering operation
may remove most of the porosity resulting in 0.01% by volume pores.
In some embodiments, the consolidation is executed by placing the
device or tube under high pressure at a temperature in the range of
a lower temperature, the lower temperature being the glass
transition temperature of the polymer, a glass transition
temperature of the polymer if the polymer exhibits more than one
(which may be the lowest, the highest, or an intermediate glass
transition temperature), or 30.degree. C. if all glass transition
temperatures of the polymer are less than 30.degree. C., and a
second higher temperature, where the second, temperature refers to
the or a melting temperature, if the polymer exhibits one or more
melting temperatures and at least one is 45.degree. C. or greater,
or alternatively, if the polymer does not have a melting
temperature, a temperature that is not greater than 20.degree. C.,
35.degree. C., or 50.degree. C. above the glass transition
temperature of the polymer (any one of multiple if multiple exist
where one of skill in the art will be able to determine the most
appropriate), or if 50.degree. C. above the highest glass
transition temperature is less than 45.degree. C., if the melting
temperature is less than 45.degree. C., or both, then 45.degree. C.
In some embodiments, the unconsolidated tube or unconsolidated
device is consolidated by the application of heat and pressure in
which the polymer is partially, or completely, melted.
As described above, solvent based methods allow for polymer
processing at lower temperatures, and thus, with lower levels of
polymer degradation. The drawback to solvent processing is that the
solvents may need to be substantially removed prior to packaging
the device. Particularly for solvents that the International
Council on Harmonization (ICH) classifies as "Class I" or "Class
II" solvents, there may be a very low limit of solvent allowed in a
medical device product. Class I solvents have unacceptable
toxicities and Class II solvents, although less toxic than Class I,
may be limited to reduce the potential of adverse events in
patients. In addition, residual solvent may act as a plasticizer in
the polymer of the device and may impact mechanical strength.
Residual solvent may migrate by diffusion to a coating on the
device, to other parts of the assembled product, such as, without
limitation, to the catheter, balloon, packaging, or a combination
thereof, for a stent that is crimped onto the balloon of a vascular
catheter and packaged. Thus, it is desirable to remove solvent to a
low level such as 2500 ppm (parts per million by weight) or lower,
1000 ppm or lower, or even 100 ppm or lower.
The various embodiments of the present invention encompass methods
of removing the residual solvent from the polymer prior to
packaging the stent, and in some embodiments, prior to the
application of a coating to the stent, such as a coating including
a drug. In some embodiments, the removal comprises heating the
polymer to and maintaining the temperature at a temperature between
the glass transition temperature (or at least 28.degree. C. if the
glass transition temperature is lower than 25.degree. C.) and an
upper temperature ("heating and maintaining operation"). In some
embodiments, the minimum temperature of the "heating and
maintaining operation" is at least 30.degree. C. or at least
32.degree. C. As used herein, the term "an upper temperature" when
used in the context of the phrase "the glass transition temperature
and an upper temperature" refers to the melting temperature, if the
polymer exhibits one or more melting temperatures and at least one
is not less than 45.degree. C., or alternatively, if the polymer
does not have a melting temperature, a temperature that is not
greater than 20.degree. C., 35.degree. C., or 50.degree. C. above
the glass transition temperature of the polymer, or 45.degree. C.,
if 50.degree. C. above the glass transition temperature of the
polymer is less than 45.degree. C., the melting temperature is less
than 45.degree. C., or both. One of skill in the art will be able
to determine the appropriate glass transition temperature and
melting temperature if the polymer exhibits more than one glass
transition temperature, more than one melting temperature, or both.
The heating and maintaining operation may be a separate operation
from additional processing operations, such as radial expansion,
axial expansion, or both, even if the temperature is the same (or
within .+-.5.degree. C.) or within the same range (between the
glass transition temperature and an upper temperature). Thus, the
heating and maintaining operation is executed in addition to, and
after the completion of, the subsequent processing operation in
which the polymer is heated to a temperature between the glass
transition temperature and an upper temperature. In some
embodiments, the temperature of the heating and maintaining
operation is between 10.degree. C. above the glass transition
temperature and 10.degree. C. below the melting temperature, if the
polymer has a melting temperature, or between 15.degree. C. above
the glass transition temperature and 15.degree. C. below the
melting temperature, if the polymer has a melting temperature and
there is more than 30.degree. C. between the glass transition
temperature and the melting temperature. If the polymer has no
melting temperature, the temperature of the heating and maintaining
temperature may be between 10.degree. C. and 45.degree. C. above
the glass transition temperature, or between 15.degree. C. and
40.degree. C. above the glass transition temperature (provided that
the glass transition and melting temperatures are greater than
25.degree. C. and 40.degree. C., respectively). The temperature of
the heating and maintaining operation may fluctuate.
In some embodiments, at least 80 weight %, at least 85 weight %, at
least 90 weight %, at least 95 weight %, at least 97 weight %, at
least 98 weight %, at least 99 weight %, or at least 99.5 weight %
of the residual solvent is removed during the execution of a
subsequent processing operation such as, without limitation, radial
expansion. In some embodiments not more than 20 weight %, not more
than 15 weight %, or not more than 10 weight % of the solvent is
removed during the subsequent processing operation. The residual
solvent may act as a plasticizer, and the plasticization may allow
processing at a lower temperature. In some embodiments, after the
execution of the subsequent processing operation, the polymer may
include at least 60 weight %, at least 70%, at least 80 weight %,
at least 90 weight %, at least 95%, 98 weight %, or 99 weight % of
the residual solvent that was in the polymer at the initiation of
the subsequent processing operation. The remaining residual solvent
may be removed (or at least 90 weight %, at least 95 weight %, or
at least 98 weight % of the remaining residual solvent) after the
execution of the subsequent processing operation, but prior to
additional processing operations, such as coating with a drug
coating, packaging, and sterilization, if any are executed.
Residual solvent may be removed to an acceptable level prior to
initiation of packaging, or prior to the initiation of a drug
coating operation.
In some embodiments, the subsequent processing operation is an
annealing operation in which the polymer is heated to and
maintained at a temperature between the glass transition
temperature (or at least 28.degree. C. if the glass transition
temperature is lower than 25.degree. C., preferably at least
30.degree. C. and in some embodiments, at least 32.degree. C.), and
an upper temperature. Annealing processes are typically performed
to allow for polymer relaxation, removal of residual stress from
processing, or both. In some embodiments, the solvent is removed
during the annealing process, that is at least 80 weight %, at
least 85 weight %, at least 90 weight %, at least 98 weight % or at
least 99 weight %, and up to 99.9999 weight % of the remaining
residual solvent is removed. In some embodiments, the duration of
the annealing process is extended beyond the time frame for polymer
relaxation, etc. to allow for solvent removal. In some embodiments,
the duration may be 1.2 times, 1.5 times, 2 times, or 3 times, and
in some embodiments, greater than 3 times, longer than would have
been required for only annealing.
In some embodiments, the heating and maintaining operation may be
performed in a convection oven. In some embodiments, the polymer is
in the form of a tube, and there is a flow of a fluid (a gas, a
liquid, or a supercritical fluid), such as air or nitrogen, through
the tube during the heating and maintaining operation. The flow may
be such that the fluid has a velocity of 0.1 to 100 m/sec. The
fluid entering the tube and before contacting the tube would be
free of, or substantially free of (not more than 2500 ppm by weight
or by volume) the solvent.
In some embodiments, the heating and maintaining operation is
executed in a vacuum, that is at a pressure below normal
atmospheric pressure (760 Torr.+-.100 Torr, preferably 760
Torr.+-.50 Torr). In some embodiments, the pressure may be at least
0.001 Torr, and not more than 400 Torr, not more than 300 Torr, not
more than 200 Torr, or more than 100 Torr, or not more than 50
Torr, but at least 0.001 Torr. The pressure may fluctuate. The
operation may be executed in a vacuum oven.
In some embodiments, the heating and maintaining, at any of the
above temperature ranges, is executed in an atmosphere with water
vapor present, that is in a high humidity environment. The high
humidity environment may be a relative humidity between 25% and
100%, preferably between 40% and 100%, and more preferably between
65% and 100%. In some embodiments, the high humidity environment
has a relative humidity between 80% and 100%. To maintain the high
humidity environment a container of water may be placed in the
environment of the polymer (such as, without limitation, an oven).
Alternatively, or additionally, there may be a stream of water
flowing in the environment of the polymer. The water, whether in a
container or flowing, may also absorb the solvent. The high
humidity environment may be at normal atmospheric pressure (760
Torr.+-.100 Torr, preferably 760 Torr.+-.50 Torr) or in a vacuum
(for example, without limitation, not more than 380 Torr or not
more than 200 Torr, but at least 0.001 Torr) as discussed above.
Water may plasticize the polymer, allowing for easier removal of
the solvent. As a non-limiting example, poly(L-lactide) absorbs up
to about 0.6-0.7 weight % water, and poly(D,L-lactide-co-L-lactide)
absorbs up to about 1.1 weight % water. For both polymers, water
acts as a plasticizer. In some embodiments, the heating and
maintaining operation is performed at a temperature below the
polymer's glass transition temperature, but not less than
28.degree. C. In some embodiments, the heating and maintaining
operation is performed at a temperature of at least 30.degree. C.,
but below the polymer's glass transition temperature (provided that
the polymer has a glass transition temperature of at least
31.degree. C.).
After most of the solvent has been removed (the solvent removal is
at least 80% complete, where complete when the specification limit
of the solvent is reached, preferably at least 90% complete, and
more preferably at least 95% complete), the water may be removed
(at least to the specification limits for the polymer, such as but
not limited to 0.1 weight %) by another heating and maintaining
operation in which the stent is placed in an environment in which
the humidity level is lower than the humidity of the high humidity
environment, and preferably an environment where the humidity is
equal to or less than 40% rh, preferably equal to or less than 30%
rh, and more preferably equal to or less than 20% rh, and at least
0.001% rh. The duration of time of the operation in a low humidity
environment may be different that the duration of the operation in
a high humidity environment. In some embodiments, the water is
removed by directing a flow of a fluid (in other words, blowing),
such as dry air or nitrogen (less than 2500 ppm water by volume, or
by weight), over, around, inside, through, adjacent to, or a
combination thereof, the polymer. For example, if the polymer is a
tube, air may be blown through, around, or both through and around
the tube. The fluid may be at a temperature in the range of
30.degree. C., to the polymer's glass transition temperature (the
polymer's glass transition temperature being the lowest glass
transition temperature that is also above 30.degree. C. if the
polymer has multiple glass transition temperatures), or to
75.degree. C., whichever is lower. In some embodiments, the fluid
is heated to the glass transition temperature of the polymer (the
polymer's glass transition temperature being the lowest glass
transition temperature that is also above 30.degree. C. if the
polymer has multiple glass transition temperatures) or just above
the glass transition temperature (within 10.degree. C. of the
polymer's glass transition temperature), provided that the polymer
has a least one glass transition temperature at or above 30.degree.
C.
In some embodiments, the heating and maintaining may be executed in
an environment of solvent vapor (removal solvent), where the
solvent is not water, but may be a blend of water and another
solvent. As used herein, with reference to placing a polymer in an
atmosphere of a solvent vapor, a solvent will refer to a substance,
including a fluid, that plasticizes, swells, or both plasticizes
and swells the polymer. Solvents may be used individually or in
combination as the removal solvent. The plasticization, swelling,
or both, of the polymer allows for easier removal of the residual
solvent. Thus, even if the polymer is exposed to another solvent,
the removal solvent, which may also need to be eventually removed,
it may be advantageous to use another solvent if it has a lower
boiling point and thus would be removed more easily, if it is a
lower health hazard, if it is a better plasticizer for the polymer
(where a "better" plasticizer lowers the glass transition more at
the same weight % of plasticizer), or any combination thereof. In
some embodiments, the removal solvent is an ICH class III solvent.
As used herein, an "ICH class III solvent" is a solvent that the
International Council on Harmonization has classified as less toxic
than class I or II solvents and is recommended for use in
production of drugs, excipients, and medicinal products instead of
Class I and Class II solvents. In some embodiments, the removal
solvent chosen would be a good solvent for the polymer where a
"good" solvent is a solvent in which polymer-solvent interactions
are stronger than polymer-polymer interactions or solvent-solvent
interactions.
In some embodiments, the removal solvent partial pressure is
between 30 Torr and 500 Torr. In some embodiments, the removal
solvent partial pressure is not less than 100 Torr. In some
embodiments, the removal solvent partial pressure is at least 25%
of the vapor pressure of the pure solvent, preferably at least 50%,
and more preferably at least 75% of vapor pressure of the pure
solvent, and may be up to the vapor pressure of the pure solvent at
the temperature of the operation. In some embodiments, the removal
solvent is above its boiling point. Preferred removal solvents are
those of a relatively low boiling point at atmospheric pressure,
that is less than or equal to 80.degree. C., and in some
embodiments, less than or equal to 60.degree. C. Some non-limiting
examples of solvents that may be useful for the polymer
poly(L-lactide), or a copolymer with L-lactide as one of the
monomers, include acetonitrile, methanol, ethanol, n-propanol,
isopropanol, butanol, fluoroform, freons, methylene chloride
(CH.sub.2Cl.sub.2), and chloroform (CHCl.sub.3). FREON.RTM. is the
trade name of DuPont for a number of chlorofluorocarbons,
chlorofluorohydrocarbons, fluoro-hydrocarbons, and halons. Halons
are hydrocarbons in which one or more hydrogen atoms are replaced
with bromine, and other hydrogen atoms with other halogen atoms
(fluorine, chlorine, and iodine). FREON.RTM. solvents include,
HFC134a.TM., the trade name for 1,1,1,2-tetrafluoroethane
(CF.sub.3CFH.sub.2), and HFC-227ea.TM., the trade name for
1,1,1,2,3,3,3-heptafluoropropane (CF.sub.3CHFCF.sub.3). HFC-134a
has a boiling point of -26.degree. C. HFC-227ea has a boiling point
of -16.degree. C. In some embodiments, the removal solvent vapor is
of a solvent that may at least partially dissolve the residual
solvent (at least 10 g/liter solubility, and preferably at least
100 g/liter solubility). Similarly to the situation with a high
humidity environment, a container of removal solvent, a flow of
removal solvent, or both, may be present in the environment of the
polymer. The removal solvent in the environment of the polymer may
absorb the residual solvent, as well as assist in maintaining the
removal solvent vapor level in the environment.
The amount of removal solvent absorbed by the polymer may be in the
range of 0.01 weight % to 20 weight %, preferably 0.02 weight % to
15 weight %, more preferably 0.1 weight % to 12 weight %, and even
more preferably 0.2 weight % to 10 weight %. In some embodiments,
amount of removal solvent absorbed by the polymer may be in the
range of 0.1% to 8 weight %, 2 weight % to 15 weight %, or 5 weight
% to 30 weight %. In some embodiments, a sufficient amount of
removal solvent is absorbed to lower the glass transition
temperature of the polymer by at least 5.degree. C., by at least
10.degree. C., by at least 15.degree. C., or by at least 20.degree.
C., but not more than 75.degree. C. A sufficient amount absorbed
may be in the range of 0.01 weight % to 50 weight %. In some
embodiments, the amount of removal solvent absorbed by the polymer,
in the range of 0.1 weight % to 35 weight %, lowers the glass
transition temperature by 5.degree. C. to 50.degree. C., or
10.degree. C. to 40.degree. C. In some embodiments, there may be a
combination of residual solvent and absorbed removal solvent which
acts as a plasticizer.
In some embodiments, the removal solvent is different from any
solvent used in production of the polymer, and different from any
solvent used in any post-production processing of the polymer. In
some embodiments, the solvent is different from a solvent used in
the immediately preceding processing operation. In some
embodiments, the removal solvent is different from any one or more
members of the group of acetone, trichloroethylene, chloroform,
dimethylacetamide, tetrahydrofuran, 2-butanone, dioxane,
tetrahydrofuran, and cyclohexanone.
In some embodiments, there is at least 30 seconds, preferably at
least 1 minute, and more preferably at least 2 minutes, between the
previous operation of processing the polymer and the heating and
maintaining operation with removal solvent vapor present. In some
embodiments, there is at least 30 minutes between the previous
operation of processing the polymer and the heating and maintaining
operation with removal solvent vapor present.
After the residual solvent is removed, then the removal solvent may
be removed from the polymer. The subsequent removal of the removal
solvent may be accomplished by a subsequent heating and maintaining
operation where no removal solvent vapor is added to the
environment, or is present in the environment. In some embodiments,
the polymer is moved to a new environment which is initially free
of, or substantially free of (<2500 ppm by weight or volume),
the removal solvent vapor. In some environments, there is a flow of
a fluid such as air or nitrogen around, inside, over, or adjacent
to the polymer, and the fluid that flows is initially (prior to
contact with the polymer or as provided to the environment of the
polymer) free of or substantially free of (<2500 ppm by weight
or volume) the removal solvent vapor. However, as the operation is
executed there will be removal solvent vapor present in the
environment due to the evaporation or diffusion from the polymer.
In some embodiments, a subsequent heating and maintaining operation
is executed for removal of the removal solvent for a duration of
time of not less than 10 minutes, and not more than 24 hours, with
the removal solvent partial pressure in the environment being less
than 50% of saturation, less than 25% of saturation, or less than
2500 ppm removal solvent vapor. In some embodiments, at least 90
weight %, at least 95 weight %, or at least 98 weight % of the
removal solvent absorbed into the polymer during the operation is
removed from the polymer. In some embodiments, the residual removal
solvent in the polymer after removal of the removal solvent, and in
some embodiments, at the initiation of packaging, is not more than
1000 ppm (parts per million by weight), not more than 500 ppm, or
not more than 100 ppm.
The duration of a heating and maintaining operation may range from
10 minutes to 240 hours or more, whether performed at normal
atmospheric pressure, in a vacuum, in a high humidity environment,
in the presence of a removal solvent vapor, or a combination
thereof. If the heating and maintaining operation in the absence of
a vacuum, a high humidity environment, or the presence of a removal
solvent vapor, the duration may be longer than if the execution
occurs in the presence of one or more of a vacuum, a high humidity
environment, and presence of a removal solvent vapor. In some
embodiments, the duration is from 10 minutes to 2 hours, from 30
minutes to 4 hours, from 1 to 10 hours, from 1 to 12 hours, from 2
to 16 hours, from 2 to 24 hours, from 4 to 48 hours, from 12 to 72
hours, or from 24 to 200 hours. In some embodiments, the duration
is between 0.2 hours and 1000 hours, 0.5 hours and 1000 hours, or 1
hour and 1000 hours.
In some embodiments, the residual solvent is removed by
supercritical fluid extraction. The polymer or polymer construct
may be placed in a chamber which is sealed, and then filled with a
flow of a fluid at or slightly above (within 5.degree. C.) its
critical temperature until the fluid reaches its supercritical
pressure, and thus is in a supercritical condition. Once a
supercritical condition is reached, a continuous flow of the fluid
through the chamber is initiated while maintaining the
supercritical conditions. The fluid exiting the chamber goes
through a restrictor valve which lowers the pressure converting the
fluid to a gas phase, with concomitant condensation of the residual
solvent. Non-limiting examples of fluids which may be used in
supercritical fluid extraction include carbon dioxide, methane,
ethane, and ethylene. The duration of the supercritical extraction
may range from 5 to 120 minutes. Carbon dioxide is preferred as the
critical temperature is between 31 and 32.degree. C.
In some embodiments, the residual solvent is removed by freeze
drying. The advantage of freeze drying is that the polymer is not
heated to a high temperature.
The polymers that are described herein for use in the embodiments
of the present invention may be used individually or in
combination.
In preferred embodiments, the polymer is Poly(L-lactide) (PLLA), a
polymer with L-lactide or L-lactic acid as a constituent monomer of
at least 30 mol %, preferably, at least 50 mol %, more preferably
60 mol %, and even more preferably at least 70 mol %, and up to 98
mol %, a polymer with L-lactide or L-lactic acid as a constituent
monomer of at least 30 mol % and having a glass transition
temperature of at least 30.degree. C., preferably at least
33.degree. C., and more preferably at least 37.degree. C., or a
combination thereof. In some embodiments, the polymer may be
poly(L-lactide-co-glycolide), poly(D,L-lactide-co-L-lactide), or a
combination thereof with the L-lactide being at least 60 mol %.
Poly(L-lactide) (PLLA) is attractive as a stent material due to its
relatively high strength and a rigidity at human body temperature,
about 37.degree. C. The glass transition temperature (Tg) of PLLA
varies between approximately 50 to 80.degree. C., or more narrowly
between 55 and 65.degree. C., depending on crystallinity,
microstructure, and molecular weight. Since typically, PLLA has
glass transition temperature between about 60 and 65.degree. C.
(Medical Plastics and Biomaterials Magazine, March 1998), it
remains stiff and rigid at human body temperature. This property
facilitates the ability of a stent to maintain a lumen at or near a
deployed diameter without significant recoil.
In some embodiments, a semicrystalline polymer may be used.
Non-limiting examples include poly(L-lactide) (PLLA), polyglycolide
(PGA), polymandelide (PM), polycaprolactone (PCL),
poly(trimethylene carbonate) (PTMC), polydioxanone (PDO),
poly(4-hydroxy butyrate) (PHB), and poly(butylene succinate) (PBS).
A non-limiting exemplary amorphous polymer that may be used as the
polymer in the embodiments of the present invention is
poly(D,L-lactide) (PDLLA). Additionally, block, random, and
alternating copolymers of the above polymers may also be used in
embodiments of the present invention, for example,
poly(L-lactide-co-glycolide).
Other preferred polymers include, without limitation, those having
a glass transition temperature of at least 30.degree. C.,
preferably at least 33.degree. C., and more preferably at least
37.degree. C., or if multiple glass transitions, the part of the
polymer having a glass transition temperature less than 30.degree.
C. comprises less than 40 weight % or less than 40 mol % of the
polymer, and preferably, less than 30 weight % or less than 30 mol
% of the polymer. Other polymers that may be used include, without
limitation, poly(glycolide), a copolymer where one constituent
monomer is glycolide, poly(DL-lactide), a copolymer where the
constituent monomers are D-lactide, L-lactide, and at least one of
the group of polydioxanone, poly(4-hydroxybutyrate), and
poly(trimethylene carbonate), a copolymer where at least one
constituent monomer is polydioxanone, poly(4-hydroxybutyrate), or
poly(trimethylene carbonate), and combinations thereof.
In some embodiments, the polymer is has an inherent viscosity of at
least 3.3 dl/g in chloroform at 25.degree. C., has a number average
molecular weight greater than 250,000 g/mole, has a weight average
molecular weight greater than 280,000 g/mole, or a combination
thereof. In some embodiments, the polymer has an inherent viscosity
of at least 4.0 dl/g, at least 4.5 dl/g, at least 5.0 dl/g, at
least 6.0 dl/g, or at least 7.0 dl/g in chloroform at 25.degree. C.
For the polymer, the upper limit of inherent viscosity may be 25
dl/g, 15 dl/g, or 10 dl/g in chloroform at 25.degree. C. The
polymer may have a number average molecular weight not greater than
1,200,000 g/mole, the polymer may have a weight average molecular
weight of not greater than 1,500,000 g/mole, or both. In some
embodiments, the polymer has a number average molecular weight
greater than 275,000 g/mole, greater than 300,000 g/mole, greater
than 350,000 g/mole, greater than 400,000 g/mole, greater than
500,000 g/mole, greater than 600,000 g/mole, or greater than
750,000 g/mole, but not greater than 2,500,000 g/mole. In some
embodiments, the polymer has a weight average molecular weight
greater than 300,000 g/mole, greater than 350,000 g/mole, greater
than 400,000 g/mole, greater than 450,000 g/mole, greater than
500,000 g/mole, greater than 675,000 g/mole, or greater than
800,000 g/mole, but not greater than 3,000,000 g/mole. In some
embodiments, a number average molecular weight (M.sub.n) or a
weight average molecular weight (M.sub.w) may be determined by Gel
Permeation Chromatography (GPC) using polystyrene standards.
In some embodiments, the stent body is formed of a polymer blended
or mixed with an absorbable metal, for example magnesium, or an
absorbable glass, such as iron doped absorbable glass. Other
additives may also be included in a medical device body.
The stent may further include a coating of one or multiple layers
disposed over the body or scaffolding having thickness of about 30
angstroms to 20 microns, preferably 30 angstroms to 10 microns, and
more preferably 150 angstroms to 5 microns. The coating may be free
of drugs, or may include a drug. In one embodiment, the coating may
be a polymer and drug mixture, which may be called a drug reservoir
layer. There may be multiple drug reservoir layers. One or more
layers may be below the drug reservoir layer, above the drug
reservoir layer, or both, and this applies to each drug reservoir
layer in the coating. In sum, there be any number of coating
layers, each of which may or may not contain a drug. As a
non-limiting example, the coating may be poly(D,L-lactide) and the
drug may be an antiproliferative, such as and without limitation,
everolimus. The coating may include other additives, or it may be
additives other than incidental migration or diffusion of other
additives in the device body into the coating. Methods of applying
coatings to substrates are well-known in the art.
Other drugs may be used in a coating over the device body, within
the device body, or a combination thereof. Drugs may be used
individually or in combination. Drugs that may be suitable for use
in the embodiments of the present invention, depending, of course,
on the specific disease being treated, include, without limitation,
anti-restenosis, pro- or anti-proliferative, anti-inflammatory,
anti-neoplastic, antimitotic, anti-platelet, anticoagulant,
antifibrin, antithrombin, cytostatic, antibiotic, anti-enzymatic,
anti-metabolic, angiogenic, cytoprotective, angiotensin converting
enzyme (ACE) inhibiting, angiotensin II receptor antagonizing, and
cardioprotective drugs. Some drugs may fall into more than one
category.
The term "anti-proliferative" as used herein, refers to a
therapeutic agent that works to block the proliferative phase of
acute cellular rejection. The anti-proliferative drug may be a
natural proteineous substance such as a cytotoxin or a synthetic
molecule. Other drugs include, without limitation,
anti-proliferative substances such as actinomycin D, and
derivatives thereof (manufactured by Sigma-Aldrich 1001 West Saint
Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN.TM. available from
Merck) (synonyms of actinomycin D include dactinomycin, actinomycin
IV, actinomycin I1, actinomycin X1, and actinomycin C1), all
taxoids such as taxols, docetaxel, paclitaxel, and paclitaxel
derivatives, FKBP-12 mediated mTOR inhibitors, and pirfenidone.
Other anti-proliferative drugs include rapamycin (sirolimus),
everolimus, zotarolimus (ABT-578), biolimus A9, ridaforolimus
(formerly deforolimus, and also known as AP23573), tacrolimus,
temsirolimus, pimecrolimus, novolimus, myolimus, umirolimus,
merilimus, 16-pent-rapamycin, 40-O-(3-hydroxypropyl)rapamycin,
40-O-[2-(2-hydroxyl)ethoxy]ethyl-rapamycin,
40-O-tetrazolylrapamycin, and 40-epi-(N1-tetrazolyl)-rapamycin.
Other compounds that may be used as drugs are compounds having the
structure of rapamycin but with a substituent at the carbon
corresponding to the 42 or 40 carbon (see structure below).
##STR00001##
Additional examples of cytostatic or antiproliferative drugs
include, without limitation, angiopeptin, and fibroblast growth
factor (FGF) antagonists.
Examples of anti-inflammatory drugs include both steroidal and
non-steroidal (NSAID) anti-inflammatories such as, without
limitation, clobetasol, alclofenac, alclometasone dipropionate,
algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac
sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen,
apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine
hydrochloride, bromelains, broperamole, budesonide, carprofen,
cicloprofen, cintazone, cliprofen, clobetasol propionate,
clobetasone butyrate, clopirac, cloticasone propionate,
cormethasone acetate, cortodoxone, deflazacort, desonide,
desoximetasone, dexamethasone, dexamethasone dipropionate,
dexamethasone acetate, dexamethasone phosphate, mometasone,
cortisone, cortisone acetate, hydrocortisone, prednisone,
prednisone acetate, betamethasone, betamethasone acetate,
diclofenac potassium, diclofenac sodium, diflorasone diacetate,
diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl
sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium,
epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen,
fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac,
flazalone, fluazacort, flufenamic acid, flumizole, flunisolide
acetate, flunixin, flunixin meglumine, fluocortin butyl,
fluorometholone acetate, fluquazone, flurbiprofen, fluretofen,
fluticasone propionate, furaprofen, furobufen, halcinonide,
halobetasol propionate, halopredone acetate, ibufenac, ibuprofen,
ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin,
indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone
acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride,
lomoxicam, loteprednol etabonate, meclofenamate sodium,
meclofenamic acid, meclorisone dibutyrate, mefenamic acid,
mesalamine, meseclazone, methylprednisolone suleptanate,
momiflumate, nabumetone, naproxen, naproxen sodium, naproxol,
nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin,
oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate
sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam,
piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate,
prifelone, prodolic acid, proquazone, proxazole, proxazole citrate,
rimexolone, romazarit, salcolex, salnacedin, salsalate,
sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac,
suprofen, talmetacin, talniflumate, talosalate, tebufelone,
tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine,
tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,
triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin
(acetylsalicylic acid), salicylic acid, corticosteroids,
glucocorticoids, tacrolimus and pimecrolimus.
Alternatively, the anti-inflammatory drug may be a biological
inhibitor of pro-inflammatory signaling molecules.
Anti-inflammatory drugs may be bioactive substances including
antibodies to such biological inflammatory signaling molecules.
Examples of antineoplastics and antimitotics include, without
limitation, paclitaxel, docetaxel, methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride
and mitomycin.
Examples of anti-platelet, anticoagulant, antifibrin, and
antithrombin drugs include, without limitation, heparin, sodium
heparin, low molecular weight heparins, heparinoids, hirudin,
argatroban, forskolin, vapiprost, prostacyclin, prostacyclin
dextran, D-phe-pro-arg-chloromethylketone, dipyridamole,
glycoprotein IIb/IIIa platelet membrane receptor antagonist
antibody, recombinant hirudin and thrombin, thrombin inhibitors
such as ANGIOMAX.RTM. (bivalirudin), calcium channel blockers such
as nifedipine, colchicine, fish oil (omega 3-fatty acid), histamine
antagonists, lovastatin, monoclonal antibodies such as those
specific for Platelet-Derived Growth Factor (PDGF) receptors,
nitroprusside, phosphodiesterase inhibitors, prostaglandin
inhibitors, suramin, serotonin blockers, steroids, thioprotease
inhibitors, triazolopyrimidine, nitric oxide, nitric oxide donors,
super oxide dismutases, super oxide dismutase mimetic and
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO).
Examples of ACE inhibitors include, without limitation, quinapril,
perindopril, ramipril, captopril, benazepril, trandolapril,
fosinopril, lisinopril, moexipril and enalapril.
Examples of angiotensin II receptor antagonists include, without
limitation, irbesartan and losartan.
Other drugs that may be used, include, without limitation,
estradiol, 17-beta-estradiol, .gamma.-hiridun, imatinib mesylate,
midostaurin, feno fibrate, and feno fibric acid.
Other drugs that have not been specifically listed may also be
used. Some drugs may fall into more than one of the above mentioned
categories. Prodrugs thereof, co-drugs thereof, and combinations
thereof of the above listed drugs are also encompassed in the
various embodiments of the present invention.
Representative examples of polymers, oligomers, and materials that
may be used, individually or in combination, in the coatings
described herein, and optionally, may be used, individually or in
combination with any other materials described herein, in forming a
medical device body, include, without limitation, polyesters,
polyhydroxyalkanoates, poly(3-hydroxyvalerate),
poly(lactide-co-glycolide), poly(3-hydroxybutyrate),
poly(4-hydroxybutyrate),
poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polyhydroxybutyrate,
polyhydroxybutyrate-co-hydroxyvalerates,
polyhydroxybutyrate-co-hydroxyhexanoate, polyorthoesters,
polyanhydrides, poly(glycolic acid), poly(glycolide), poly(L-lactic
acid), poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide),
poly(L-lactide-co-D,L-lactide), poly(caprolactone),
poly(L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone),
poly(D-lactide-co-caprolactone), poly(D-lactide),
poly(glycolide-co-caprolactone), poly(trimethylene carbonate),
polyester amides, poly(glycolic acid-co-trimethylene carbonate),
poly(amino acid)s, polyphosphazenes, polycarbonates, cellulose
acetate, cellulose butyrate, cellulose acetate butyrate,
cellophane, cellulose nitrate, cellulose propionate, cellulose
ethers, silk-elastin, elastin mimetic peptides, alginic acid,
alginate, chondroitin sulfate, chitosan, chitosan sulfate,
collagen, fibrin, fibrinogen, cellulose, cellulose sulfate,
carboxymethylcellulose, hydroxyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose (HPMC),
carboxymethylcellulose sodium, hydroxyethylcellulose, gelatin,
sugars, starch, modified starches, such as hydroxyethyl starch and
2-O-acetyl starches), polysaccharides, dextran sulfate, dextran,
dextrin, xanthan, hyaluronic acid, fragments of hyaluronic acid,
polysaccharides, and copolymers thereof.
As used herein, the terms poly(D,L-lactide), poly(L-lactide),
poly(D,L-lactide-co-glycolide), and poly(L-lactide-co-glycolide)
are used interchangeably with the terms poly(D,L-lactic acid),
poly(L-lactic acid), poly(D,L-lactic acid-co-glycolic acid), and
poly(L-lactic acid-co-glycolic acid), respectively.
As used herein, caprolactone includes, but is not limited to,
.epsilon.-caprolactone.
For the purposes of the present invention, the following terms and
definitions apply:
As used herein, "particle" is a piece of matter held together by
physical bonding of molecules, an agglomeration of pieces of matter
("particles") held together by colloidal forces and/or surface
forces, a piece of matter which is held together by chemical bonds
such as a cross-linked polymer network, a piece of matter formed by
ionic interactions, or a piece of matter held together by any
combination of agglomeration, surface forces, colloidal forces,
ionic interactions, and chemical bonds. For the purposes of this
disclosure, a particle will be defined as ranging in size from less
than a one tenth of a nanometer to several millimeters in size.
The average diameter of a group of particles depends upon the
measurement technique used. In addition, the particular shape of
the particles may impact the measured average diameter. For example
a sieving method works well for particles that are spherical but
for rod-like particles, a sieve representing a particular particle
size fraction will retain some rod-like particles while others will
pass through as they move through the sieve along the short axis.
Thus, the same sized particles may end up on different sieves.
Particle diameters may be expressed as a number average particle
diameter, a surface area average particle diameter, or a volume
average particle diameter. The general formula for the number
average diameter for a group of particles is expressed as
d.sub.n=.SIGMA..sub.i n.sub.id.sub.i/.SIGMA..sub.i n.sub.i where
d.sub.i is the diameter assigned to a class of particles, say
d.sub.i=0.5 .mu.m for the class of particles from 0 to 1 .mu.m, and
n.sub.i represents the number of particles in the category. Using
the same classification structure, that is placing the particles in
groups and using an appropriate d.sub.i to represent the group, the
surface area and volume average diameters are expressed by
d.sub.s=(.SIGMA..sub.i n.sub.id.sub.i.sup.2/.SIGMA..sub.i
n.sub.i).sup.1/2 and d.sub.v=(.SIGMA..sub.i
n.sub.id.sub.i.sup.3/.SIGMA..sub.i n.sub.i).sup.1/3.
As used herein, if not otherwise specified, the average particle
diameter will refer to the diameter determined by dynamic light
scattering, that is photon correlation spectroscopy, based on the
assumption that the particles observed are spherical, or coulter
counting. The average diameter as determined by dynamic light
scattering diameters may be the "z average" diameter which
represents the mean hydrodynamic diameter. One method for
calculating the z-average diameter from dynamic light scattering
measurements is provide in the International Standards Organization
("ISO") 13321.
"Compression molding" is a method of molding in which the molding
material, generally preheated, is first placed in an open, heated
mold cavity. The mold is closed with a top force or plug member,
pressure is applied to force the material into contact with all
mold areas, and heat and pressure are maintained until the molding
material has cured. The process may employ thermosetting resins in
a partially cured stage, either in the form of granules, putty-like
masses, or preforms. A polymer construct may be formed by
compression molding.
"Ram extrusion" refers to a process in which a resin is fed from a
hopper and packed into a cylinder in repeated increments by a
reciprocating plunger. The frequency and amplitude of the plunger
stroke can be controlled by an oil hydraulic system. The compressed
material moves through a heated zone where it is fused into a
profile matching the cross section of the barrel or die. The output
rate is proportional to the length and frequency of the ram
strokes. Die length, electrical heater capacity, hydraulic system
power and maximum force, and the strength of the construction
materials determine equipment capability.
"Gel extrusion", also known as phase separation or extraction or
wet process, is a process in which a polymer fluid, including a
polymer mixed with a solvent, is extruded. The polymer has a
viscosity low enough to be extruded at temperatures below the
melting point of the polymer.
As used herein, a "polymer" refers to a molecule comprised of,
actually or conceptually, repeating "constitutional units." The
constitutional units derive from the reaction of monomers. As a
non-limiting example, ethylene (CH.sub.2.dbd.CH.sub.2) is a monomer
that can be polymerized to form polyethylene,
CH.sub.3CH.sub.2(CH.sub.2CH.sub.2).sub.nCH.sub.2CH.sub.3 (where n
is an integer), wherein the constitutional unit is
--CH.sub.2CH.sub.2--, ethylene having lost the double bond as the
result of the polymerization reaction. Although poly(ethylene) is
formed by the polymerization of ethylene, it may be conceptually
thought of being comprised of the --CH.sub.2-- repeating unit, and
thus conceptually the polymer could be expressed by the formula
CH.sub.3(CH.sub.2).sub.mCH.sub.3 where m is an integer, which would
be equal to 2n+2 for the equivalent number of ethylene units
reacted to form the polymer. A polymer may be derived from the
polymerization of two or more different monomers and therefore may
comprise two or more different constitutional units. Such polymers
are referred to as "copolymers." "Terpolymers" are a subset of
"copolymers" in which there are three different constitutional
units. The constitutional units themselves can be the product of
the reactions of other compounds. Those skilled in the art, given a
particular polymer, will readily recognize the constitutional units
of that polymer and will equally readily recognize the structure of
the monomer or materials from which the constitutional units
derive. Polymers may be straight or branched chain, star-like or
dendritic, or one polymer may be attached (grafted) onto another.
Polymers may have a random disposition of constitutional units
along the chain, the constitutional units may be present as
discrete blocks, or constitutional units may be so disposed as to
form gradients of concentration along the polymer chain. Polymers
may be cross-linked to form a network.
As used herein, a polymer has a chain length of 50 constitutional
units or more, and those compounds with a chain length of fewer
than 50 constitutional units are referred to as "oligomers." As
used to differentiate between oligomers and polymers herein, the
constitutional unit will be the smallest unique repeating unit. For
example, for poly(lactide) the constitutional unit would be
##STR00002## even though the polymer may be formed by the reaction
of the cyclic dimer, lactide,
##STR00003## Similarly, for poly(ethylene) the constitutional unit
used to count the "number" of constitutional units would be the
number of --CH.sub.2-- units, even though conventionally the
constitutional unit is stated to be --CH.sub.2CH.sub.2-- because it
is always derived from the reaction of ethylene.
"Molecular weight" can refer to the molecular weight of individual
segments, blocks, or polymer chains. "Molecular weight" can also
refer to weight average molecular weight or number average
molecular weight of types of segments, blocks, or polymer
chains.
The number average molecular weight (M.sub.n) is the common, mean,
average of the molecular weights of the individual segments,
blocks, or polymer chains. It is determined by measuring the
molecular weight of N polymer molecules, summing the weights, and
dividing by N:
.times..times..times. ##EQU00001## where N.sub.i is the number of
polymer molecules with molecular weight M.sub.i. The weight average
molecular weight is given by:
.times..times..times..times. ##EQU00002## where N.sub.i is the
number of molecules of molecular weight M.sub.i. Another commonly
used molecular weight average is the viscosity average molecular
weight which may be expressed as the following:
.upsilon..times..alpha..times..times..times..alpha. ##EQU00003##
where a is typically less than 1, and is related to intrinsic
viscosity.
The "inherent viscosity" (of a polymer) is the ratio of the natural
logarithm of the relative viscosity, .eta.r, to the mass
concentration of the polymer, c, i.e. .eta.inh=(ln .eta.r)/c, where
the relative viscosity (.eta.r) is the ratio of the viscosity of a
polymer solution, .eta., to the viscosity of the solvent (.eta.s),
.eta.r=.eta./.eta.s.
The "glass transition temperature," T.sub.g, is the temperature at
which the amorphous domains of a polymer change from a brittle,
vitreous state to a solid deformable state (or rubbery state) at a
given pressure. In other words, the T.sub.g corresponds to the
temperature where the onset of segmental motion in the chains of
the polymer occurs. The measured T.sub.g of a given polymer can be
dependent on the heating rate and can be influenced by the thermal
history, and potentially pressure history, of the polymer, as well
as potentially the pressure at which the measurement is made.
T.sub.g is also affected by other compounds mixed with the polymer,
such as, without limitation, fillers, or residual solvent, etc. The
chemical structure of the polymer heavily influences the glass
transition by affecting mobility. As used herein the glass
transition temperature of the polymer will refer to the glass
transition temperature of the polymer as measured by standard
differential scanning calorimetry (modulated or unmodulated) with a
temperature ramp of 5-20.degree. C./min and if modulated, with a
temperature modulation of 0.01 to 2.degree. C. with a modulation
period of 1 to 100 seconds, utilizing nitrogen or argon at a flow
rate of 10-200 ml/min.
The "melting temperature," T.sub.m, of a polymer is the temperature
at which an endothermal peak is observed in a DSC measurement, and
where at least some of the crystallites begin to become disordered.
The measured melting temperature may occur over a temperature range
as the size of the crystallites, as well as presence of impurities,
plasticizers, or a combination thereof, impacts the measured
melting temperature of a polymer.
As used herein, a reference to the crystallinity of a polymer
refers to the crystallinity as determined by standard DSC
techniques.
Plasticization refers to the addition of a second, lower T.sub.g
substance, which is generally lower molecular weight material, to a
polymer where the substance is at least partially miscible with the
polymer. The effect is to lower the T.sub.g of the blend, and
generally, also to transform a hard, brittle material to a soft,
rubber-like material. According to the free volume model, the
plasticizer, that is the second lower T.sub.g and generally lower
molecular weight material, added to the polymer, has a higher free
volume. The addition of a higher free volume material to the
polymer increases the "free volume" of the blend, and allows for
greater polymer chain mobility, thus lowering the T.sub.g. An
alternative view, based on a lattice model similar to that used by
Flory and Huggins, is that the true thermodynamic T.sub.g is the
point of zero configurational entropy. Thus, in this model, the
lower T.sub.g resulting from the addition of a second smaller
molecule is due to the larger number of potential configurations of
the polymer chains with the presence of the smaller molecule when
compared to the number of potential configurations with only the
long chain polymer molecules. Thus, regardless of the theoretical
explanation for plasticization, the uptake of a plasticizer would
tend to allow for greater polymer chain mobility, and as a result,
a lower T.sub.g.
"Stress" refers to force per unit area, as in the force acting
through a small area within a plane. Stress can be divided into
components, normal and parallel to the plane, called normal stress
and shear stress, respectively. True stress denotes the stress
where force and area are measured at the same time. Conventional or
engineering stress, as applied to tension and compression tests, is
force divided by the original gauge length.
"Strength" refers to the maximum stress along an axis which a
material will withstand prior to fracture. The ultimate strength is
calculated from the maximum load applied during the test divided by
the original cross-sectional area.
"Radial strength" of a stent is defined as the pressure at which a
stent experiences irrecoverable deformation. The loss of radial
strength is followed by a gradual decline of mechanical
integrity.
"Modulus" may be defined as the ratio of a component of stress or
force per unit area applied to a material divided by the strain
along an axis of applied force that results from the applied force.
The modulus is the initial slope of a stress-strain curve, and
therefore, determined by the linear hookean region of the curve.
For example, a material has a tensile, a compressive, and a shear
modulus.
"Strain" refers to the amount of elongation or compression that
occurs in a material at a given stress or load, or in other words,
the amount of deformation.
"Elongation" may be defined as the increase in length in a material
which occurs when subjected to stress. It is typically expressed as
a percentage of the original length.
"Toughness" is the amount of energy absorbed prior to fracture, or
equivalently, the amount of work required to fracture a material.
One measure of toughness is the area under a stress-strain curve
from zero strain to the strain at fracture. The units of toughness
in this case are in energy per unit volume of material.
As used herein, a "drug" refers to a substance that, when
administered in a therapeutically effective amount to a patient
suffering from a disease or condition, has a therapeutic beneficial
effect on the health and well-being of the patient. A therapeutic
beneficial effect on the health and well-being of a patient
includes, but is not limited to, any one or more of the following:
(1) curing the disease or condition; (2) slowing the progress of
the disease or condition; (3) causing the disease or condition to
retrogress; (4) alleviating one or more symptoms of the disease or
condition.
As used herein, a "drug" also includes any substance that when
administered to a patient, known or suspected of being particularly
susceptible to a disease, in a prophylactically effective amount,
has a prophylactic beneficial effect on the health and well-being
of the patient. A prophylactic beneficial effect on the health and
well-being of a patient includes, but is not limited to, any one or
more of the following: (1) preventing or delaying on-set of the
disease or condition in the first place; (2) maintaining a disease
or condition at a retrogressed level once such level has been
achieved by a therapeutically effective amount of a substance,
which may be the same as or different from the substance used in a
prophylactically effective amount; (3) preventing or delaying
recurrence of the disease or condition after a course of treatment
with a therapeutically effective amount of a substance, which may
be the same as or different from the substance used in a
prophylactically effective amount, has concluded.
As used herein, "drug" also refers to pharmaceutically acceptable,
pharmacologically active salts, esters, amides, and the like, of
those drugs specifically mentioned herein.
As used herein, a material that is described as "disposed over" an
indicated substrate refers to, e.g., a coating layer of the
material deposited directly or indirectly over at least a portion
of the surface of the substrate. Direct depositing means that the
coating layer is applied directly to the surface of the substrate.
Indirect depositing means that the coating layer is applied to an
intervening layer that has been deposited directly or indirectly
over the substrate. A coating layer is supported by a surface of
the substrate, whether the coating layer is deposited directly, or
indirectly, onto the surface of the substrate. The terms "layer"
and "coating layer" will be used interchangeably herein. A "layer"
or "coating layer" of a given material is a region of that material
whose thickness is small compared to both its length and width
(e.g., the length and width dimensions may both be at least 5, 10,
20, 50, 100 or more times the thickness dimension in some
embodiments). As used herein a layer need not be planar, for
example, taking on the contours of an underlying substrate. Coating
layers can be discontinuous. As used herein, the term "coating"
refers to one or more layers deposited on a substrate. A coating
layer may cover all of the substrate or a portion of the substrate,
for example a portion of a medical device surface. Typically, a
coating layer does not provide a significant fraction of the
mechanical support for the device, but a number (including one) of
layers of material combined may form a device body, if sufficiently
thick, or a device body or substrate may be a multi-laminate
structure. In some embodiments, the layers differ from one another
in the type of materials in the layer, the proportions of materials
in the layer, or both. In some embodiments, a layer may have a
concentration gradient of the components. One of skill in the art
will be able to differentiate different coating layers or regions
from each other based on the disclosure herein.
As used herein, "above" a surface or layer is defined as further
from the substrate measured along an axis normal to a surface, or
over a surface or layer, but not necessarily in contact with the
surface or layer.
As used herein, "below" a surface or layer is defined as closer to
the substrate measured along an axis normal to a surface, or under
a surface or layer, but not necessarily in contact with the surface
or layer.
While particular embodiments of the present invention have been
shown and described, it will be obvious to those skilled in the art
that changes and modifications can be made without departing from
this invention in its broader aspects. Therefore, the claims are to
encompass within their scope all such changes and modifications as
fall within the true spirit and scope of this invention. Moreover,
although individual aspects or features may have been presented
with respect to one embodiment, a recitation of an aspect for one
embodiment, or the recitation of an aspect in general, is intended
to disclose its use in all embodiments in which that aspect or
feature can be incorporated without undue experimentation. Also,
embodiments of the present invention specifically encompass
embodiments resulting from treating any dependent claim which
follows as alternatively written in a multiple dependent form from
all prior claims which possess all antecedents referenced in such
dependent claim (e.g. each claim depending directly from claim 1
should be alternatively taken as depending from any previous
claims).
* * * * *
References